Decoding the spatiotemporal characteristics of ferroptosis: reshaping tumour therapeutic strategies.

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Learn more: PMC Disclaimer | PMC Copyright Notice Exp Hematol Oncol . 2026 Apr 8;15:42. doi: 10.1186/s40164-026-00773-5 Search in PMC Search in PubMed View in NLM Catalog Add to search Decoding the spatiotemporal characteristics of ferroptosis: reshaping tumour therapeutic strategies Lizhou Song Lizhou Song 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China 3 School of Anesthesiology, Hebei North University, Hebei, 075000 China Find articles by Lizhou Song 1, 2, 3, # , Yue Shu Yue Shu 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China 3 School of Anesthesiology, Hebei North University, Hebei, 075000 China Find articles by Yue Shu 1, 2, 3, # , Tian Zhou Tian Zhou 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China Find articles by Tian Zhou 1, 2, # , Yi Wang Yi Wang 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China Find articles by Yi Wang 1, 2, # , Haoling Zhang Haoling Zhang 4 Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, 13200 Malaysia Find articles by Haoling Zhang 4 , Yan Liao Yan Liao 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China Find articles by Yan Liao 1, 2, ✉ , Chenglong Zhu Chenglong Zhu 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China Find articles by Chenglong Zhu 1, 2, ✉ , Wangzheqi Zhang Wangzheqi Zhang 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China Find articles by Wangzheqi Zhang 1, 2, ✉ , Zui Zou Zui Zou 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China Find articles by Zui Zou 1, 2, ✉ Author information Article notes Copyright and License information 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433 China 2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433 China 3 School of Anesthesiology, Hebei North University, Hebei, 075000 China 4 Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, 13200 Malaysia ✉ Corresponding author. # Contributed equally. Received 2025 Dec 5; Accepted 2026 Apr 1; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13067480  PMID: 41952187 Abstract The resistance to treatment and the high chance of death associated with cancer still remain key problems that need breakthrough in biology and medicine. Ferroptosis is a newly discovered form of regulated cell death that is driven by iron and lipid peroxidation. Research reveals that ferroptosis plays an important role in tumour initiation, progression, and treatment. Furthermore, this process is mediated by distinct and dynamic molecular mechanisms. All of this information about the importance of ferroptosis will provide new targets and opportunities for cancer therapies. Cross-talk with other cell death pathways (e.g. apoptosis, necroptosis, autophagy) can modulate ferroptosis, and in some contexts these interactions may inhibit ferroptosis execution or activate adaptive survival responses in tumour cells. Ferroptosis has an initiation stage, a subsequent execution stage, and lastly a termination stage. Moreover, the sensitivity and response mechanisms of tumour cells to ferroptosis have significant differences in the early stage, progressive stage, metastatic stage, recurrent stage, etc. Due to the heterogeneous microenvironmental characteristics of hypoxic regions, immune-infiltrated regions and fibrotic regions in the spatial area of the tumour microenvironment (TME), these regions dynamically interact with ferroptosis. At present, strategies based on ferroptosis for tumour therapy have shown great promise. The use of advanced stimulus-responsive nanotechnology with classical ferroptosis inducers will enable the precise delivery and slow release of these inducers to enhance therapeutic efficacy and minimise damage to normal tissues. Nonetheless, several hurdles remain for clinical translation. A detailed examination of the complex regulatory networks in the TME, the development of scalable manufacturing processes for nanosystems, and the identification of non-invasive biomarkers to monitor the efficacy of ferroptosis are critical breakthrough points in the translation of ferroptosis-based therapy from bench to bedside. Graphical Abstract Keywords: Ferroptosis, Temporal specificity, Spatial specificity, Regulation of ferroptosis, TME, Nanotechnology Introduction One of the top killers among patients today is cancer. Despite ongoing development and application of both traditional therapeutic modalities (such as surgery, radiotherapy and chemotherapy) and newly developed treatment approaches (including targeted therapy and immunotherapy), the clinical efficacy of cancer therapies remains inadequate. This deficiency is primarily attributed to significant challenges, including high tumour heterogeneity, drug resistance, high rates of recurrence, and immune escape [ 1 ]. As a result, the development of new means to induce tumour cell death and their translation into clinical cancer therapy have become a central issue in the field of tumour biology and clinical medicine. Ferroptosis refers to a new form of regulated cell death (RCD) that manifests as the irreversible accumulation of lipid peroxidation that depends on iron. Since its formal definition in 2012 [ 2 ], ferroptosis has received increased attention in the life sciences as a result of its importance in tumour biology and therapy. As shown in Fig. 1 , ferroptosis discovery and naming timeline, as well as expected future experimental directions and clinical application of this type of cell death for therapy of diseases. Ferroptosis is characterized by dysfunctional accumulation of intracellular reactive oxygen species (ROS), disruption of the lipid bilayer structure and morphological changes in mitochondria with a reduced number of cristae and increased membrane density [ 2 , 3 ]. Research has shown that in the early process of ferroptosis, when the cystine/glutamate antiporter system (System xc − ) and its subunits are inhibited, cystine deprivation occurs. In turn, this cystine deprivation blocks the intracellular synthesis of glutathione (GSH). Ferroptosis requires this in order to occur [ 4 , 5 ]. Unlike that, rupture of cell membrane and transmission of ferroptotic signals to neighbouring cells primarily happen at the late stage of ferroptosis [ 6 – 8 ]. Ferroptosis exerts distinct functions at different stages of tumour development: the majority of studies indicate that during tumour metastasis, ferroptosis suppresses epithelial-mesenchymal transition in tumour cells and eliminates circulating tumour cells, thereby inhibiting tumour metastasis and recurrence [ 9 , 10 ]. However, other studies indicate that in the early stages of tumours, ferroptotic tumour cells release 8-hydroxy-2′-deoxyguanosine, a substance capable of activating the stimulus-triggered intron 173/interferon gene-stimulated (STING) dependent deoxyribonucleic acid (DNA) sensor pathway in macrophages. This pathway induces macrophage activation and drives the early progression of pancreatic ductal adenocarcinoma [ 11 ]. In addition, the regional traits of tumour microenvironment (TME) significantly influence the crosstalk between ferroptosis and tumours. The low pH environment in hypoxic regions of the TME may mediate tumour cell drug resistance through hypoxia-inducible factor (HIF)-1α [ 12 , 13 ]. In immune-infiltrated regions of the TME, immune cells may exert additional tumouricidal effects by inducing ferroptosis [ 14 ]. These interactions between ferroptosis and tumour cells involve various time dimensions (e.g. tumour development stage) and space dimensions (e.g. TME region), which suggests that the designing of cancer therapeutic strategies relying on the spatiotemporal characteristics of ferroptosis and tumour initiation/ progression have significant translational potential. Fig. 1. Open in a new tab Discovery, naming, research history of molecular mechanisms, and research directions of clinical translation of ferroptosis. This figure illustrates the timeline of ferroptosis research, categorized into distinct stages. The early clue stage (1990s): The key observation during this period was that Cys depletion was found to induce neuronal death, providing initial hints for ferroptosis research. Key discovery stage (2003–2012). The conceptual foundation of ferroptosis was established through a series of seminal observations over nearly a decade. In 2003, the small molecule erastin was reported to induce a non-apoptotic form of cell death, distinct from any previously characterized pathway. Subsequent studies between 2007 and 2008 revealed that iron chelators could effectively prevent erastin-induced lethality, suggesting an iron-dependent mechanism. These discoveries culminated in 2012, when this unique form of RCD was formally defined as ferroptosis—a process driven by lipid peroxidation and mechanistically separate from apoptosis. Mechanistic elucidation stage (2012–2020). Following its definition, research rapidly advanced toward delineating the molecular circuitry underlying ferroptosis. During this period, both inhibitory and activating pathways were progressively identified, including key antioxidant systems and iron–lipid metabolic regulators, thereby establishing the mechanistic framework that now supports its functional exploration across diverse disease contexts. Application expansion stage (since 2020): It has been demonstrated that ferroptosis can be applied to the treatment of various diseases, including cancer, neurological, cutaneous, haematological, and immunological diseases. Additionally, precise regulation of ferroptosis can be achieved through genetic technologies, nanotechnologies, and other approaches. Currently, ferroptosis research is entering a new field.Cys: cysteine; PUFAs: polyunsaturated fatty acids; GPX4: glutathione peroxidase 4; System Xc − : cystine/glutamate antiporter system; GSH: glutathione; FSP1: ferroptosis suppressor protein 1; BH4: tetrahydrobiopterin; CoQ 10 : Coenzyme Q 10 ; Nrf2: nuclear factor E2-related factor 2; GCH1: GTP cyclohydrolase 1; HIF-1α: hypoxia-inducible factor-1 α In conclusion, ferroptosis-based strategies constitute a rapidly expanding platform for cancer therapeutics. The temporal characteristics of ferroptosis, its stage-specific patterns during tumour growth, and the spatial heterogeneity across microscale niches of TME together provide a dynamic framework for understanding tumour susceptibility. The perspective on tumour susceptibility dynamics is not only multidimensional but also time-varying, opening new pathways for the mechanistically informed design of therapeutics. With nano-technology incorporated, the ferroptosis-targeted agents to achieve enhanced spatial and temporal control. These advancements will notably speed up the transfer from bench-based experiments and actual applications from the auspices of ferroptosis modelling designs. Core mechanisms of ferroptosis Ferroptosis is primarily centered around the combination of three processes. Disturbed iron homeostasis leads to excessive lipid peroxides (LPO) and impaired antioxidants that damage cells [ 3 , 15 – 17 ]. Iron metabolism serves as the initial trigger that balances the equilibrium of all cellular iron intake, transport and storage and export [ 18 ]. Unprocessed iron expands the pool of more toxic iron within cells. This, further, causes these cells to catalyse several Fenton-type reactions. These reactions give rise to ROS, whose presence induces destructive ferroptosis. The second execution stage involves lipid peroxidation, which depends on the availability of polyunsaturated fatty acid (PUFA)-containing phospholipids and the propagation of peroxidation chain reactions in cell membranes [ 19 ]. When malfunction of antioxidants defences occurs then the oxidative cascade increases. Three principal protective systems have been identified: (1) the canonical System xc − -GSH-glutathione peroxidase 4 (GPX4) axis [ 17 , 18 ]; (2) the ferroptosis suppressor protein 1 (FSP1)–coenzyme Q 10 (CoQ 10 ) pathway [ 20 , 21 ]; and (3) the guanosine triphosphate cyclohydrolase 1 (GCH1)–tetrahydrobiopterin (BH4) system [ 18 , 22 ]. Collectively, the combination of these pathways is considered to determine the redox threshold for ferroptotic death initiation or inhibition. Table 1 illustrates an overview of the transcriptional and epigenetic regulatory mechanisms of ferroptosis-associated genes. Table 1. Transcriptional and epigenetic regulatory network of ferroptosis-related genes Regulatory hierarchy Key regulatory factor Target gene/ pathway Regulatory mechanism Experimental validation method Related disease/ model Ref. Transcriptional regulation NFE2L2/Nrf2 GPX4, SLC7A11, FTH1 Binding of ARE elements to activate antioxidant genes. Chlp-seq, luciferase reporter gene Lung cancer [ 33 – 37 , 236 ] Epigenetics KDM6A ACSL4, ETNK1 Demethylation of histone H3K27me3 activates ferroptosis genes. RNA-seq, Chlp-seq PC [ 161 , 237 – 241 ] Non-coding RNA miR-522 ALOX15 Exosome delivery, inhibiting target gene expression RNA. Pull-down, fluorescence in situ hybridization GC [ 197 , 242 ] RNA modification m6A (YTHDF2) SLC2A3 Regulates mRNA stability and affects glucose metabolism. MeRIP-seq, RIP-qPCR Lung adenocarcinoma [ 183 , 242 ] Chromatin conformation PCIF1 FTH1, SLC3A2, CD69 M6Am Modulates T Cell Ferroptosis and Activation. Hi-C, ATAC-seq Melanoma [ 191 , 243 ] Long chain non-coding RNA DACT3-AS1 SIRT1 Binds to miR-181a-5p, upregulates SIRT1 to promote ferroptosis. RNA-seq, luciferase reporter gene GC [ 202 , 242 ] Circular RNA circIL4R GPX4 Binding to miR-541-3p upregulates GPX4. CircRNA sequencing, RIP HCC [ 244 – 246 ] Histone modification H3K9me3 SLC3A2 Upregulate SLC3A2 expression to inhibit ferroptosis. ChIP-seq NSCLC [ 242 , 247 ] DNA methylation DNA methyltransferase 1 SLC7A11 High methylation suppresses SLC7A11 expression. Methylation-specific PCR, bisulfite sequencing Lung cancer [ 248 ] Open in a new tab Core pathways of ferroptosis The ferroptosis regulatory framework consists of three interconnected axes: the System xc − -GSH-GPX4 antioxidant pathway, iron metabolism, and lipid metabolism. The aforementioned core pathways establish the biochemical milieu that confers ferroptotic vulnerability. Figure 2 gives an overview of their mechanistic interrelations. Fig. 2. Open in a new tab Core molecular mechanism of ferroptosis. This figure illustrates the core molecular mechanism of ferroptosis, which involves three major metabolic pathways: the System xc − -GSH-GPX4 antioxidant pathway (the primary inhibitory pathway of ferroptosis), iron metabolism (where Fe 2+ promotes lipid peroxidation via the Fenton reaction), and lipid metabolism (in which ACSL4/LPCAT3 mediate the synthesis of ferroptosis-sensitive PLs, specifically polyunsaturated fatty acid-containing PLs). The FSP1-CoQ 10 -NAD(P)H and GCH1-BH4 pathways operate as parallel antioxidant defences, independently counteracting lipid peroxidation and thereby restraining ferroptotic execution. In contrast, p53 and BAP1 sensitize cells to ferroptosis primarily through repression of System xc − mediated cystine import. HIF-1α, however, exerts a more nuanced influence, functioning as either a suppressor or facilitator depending on the cellular metabolic state and oxygen availability System Xc − : cystine/glutamate antiporter system; GSH: glutathione; GPX4: glutathione peroxidase 4; Cys: cysteine; Glu: Glutamic acid; GCL: glutamate-Cys ligase; GSS: glutathione synthetase; HIF-1α: hypoxia-inducible factor-1 α; BAP1: BRCA1-associated protein 1; LPO: lipid peroxides; SLC7A11: solute carrier family 7 member 11; SLC3A2: solute carrier family 3 member 2; PLOOH: phospholipid hydroperoxide; PLOH: reduced lipid peroxides; FSP1: ferroptosis suppressor protein 1; CoQ 10 : Coenzyme Q 10 ; NAD(P)H: nicotinamide adenine dinucleotide phosphate; FAD: flavin adenine dinucleotide; FADH 2 : reduced flavin adenine dinucleotide; LOH: lipid alcohols; LOO·: lipid peroxidation free radicals; GCH1: GTP cyclohydrolase 1; GTP: guanosine triphosphate; DHNP: 7,8-dihydroneopterin 3’-phosphate; BH4: tetrahydrobiopterin; RTA: radical-trapping antioxidants; PUFAs: polyunsaturated fatty acids; TR1: transferrin receptor 1; Tf: transferrin; DMT1: divalent metal transporter 1; STEAP3: six-transmembrane epithelial antigen of the prostate 3; LIP: labile iron pool; R’-OOH: organic hydroperoxide; CoA: coenzyme A; ACSL4: acyl-CoA synthetase long-chain family member 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; MUFAs: monounsaturated fatty acids; PE: phosphatidylethanolamine; PLs: phospholipids System xc − - GSH - GPX4 System xc − , a cystine/glutamate antiporter embedded in the plasma membrane, comprises the light-chain subunit SLC7A11 and the heavy-chain component Solute Carrier Family 3 member 2 (SLC3A2, also known as 4F2hc) [ 23 ]. GSH is an important antioxidant within cells. It regulates redox balance by scavenging LPO. This stops the spread of lipid peroxidation [ 24 ]. GPX4 utilizes GSH as a cofactor to convert phospholipid hydroperoxides (PLOOHs) into reduced phospholipid hydroperoxides (PLOHs) and prevents lipid peroxidation chain reactions [ 25 ]. Erastin, which blocks cystine-glutamate transport, is a selective inhibitor of System xc − that induces the depletion of intracellular GSH and thereby promotes ferroptosis [ 4 ]. System xc⁻ imports cystine for GSH synthesis; GPX4 uses GSH to reduce lipid hydroperoxides and thereby prevents lethal membrane peroxidation. As a classical suppressive pathway in ferroptosis biology, the System xc − -GSH-GPX4 axis is still a major target in preclinical studies aiming to manipulate tumour susceptibility to ferroptosis, providing a basis for therapeutic strategies designed to enhance ferroptosis in cancer therapy. Iron metabolism At the level of iron metabolism regulation, cells primarily uptake iron via the transferrin (Tf)-transferrin receptor (TfR)1 pathway: Fe 3+ in serum first binds to Tf to form a complex, which then enters the cell through TfR1-mediated endocytosis [ 26 ]. Fe 3+ is reduced to Fe 2+ by the enzyme six-transmembrane epithelial antigen of the prostate 3 (STEAP3) in intracellular endocytic vesicles, releasing Fe²⁺ into the cytoplasm via divalent metal transporter 1 (DMT1) to create the labile iron pool (LIP) [ 27 ]. The presence of endogenous intracellular lipids can cause free radicals to be generated. In turn, the free radicals generate a reaction. The reaction in question is Fenton reaction. Moreover, the reaction activates lipid peroxidation cascades. The other result is that the end-stage of the disease is cancer cell ferroptosis [ 28 ]. Ferroportin (FPN) is an important regulator of ferroptosis. FPN is known to be the only transmembrane exporter that mediates iron efflux, a function critical in regulating ferroptosis-associated neurodegeneration, 77% of intracellular iron is exported via FPN [ 29 ]. Lipid metabolism The lipid metabolic axis that modulates the levels of PUFAs and MUFAs in cellular membranes mainly governs the lipid peroxidation process that characterizes ferroptosis [ 19 ]. The membrane’s oxidative injury is affected by this regulatory balance. Among PUFAs, arachidonic acid (AA) is first esterified to coenzyme A (CoA) by long-chain acyl-CoA synthetase (ACSL) 4 to generates acyl-CoA. Subsequently, it is incorporated into phosphatidylethanolamine (PE) by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to produce PUFA-PE. PUFA-PE is the main substrate for lipid peroxidation reactions [ 30 ]. On the contrary, MUFAs act as endogenous antagonists of it. Activation of ACSL3 result in the deposition of MUFA into membrane phospholipids (PLs) at the expense of PUFA-PE formation, which prevents lipid peroxidation propagation and confers ferroptosis resistance [ 31 ]. The relative activities of ACSL4 and ACSL3 and the compositional ratio of PUFA-PE to MUFA-PE in membrane PLs act as a molecular rheostat that regulates vulnerability to ferroptosis. Recent studied have confirmed that LPO is mitochondria-driven. The crosstalk between CCN1 and electron transfer flavoprotein subunit alpha (ETFA) in mitochondria facilitates fatty acid beta-oxidation (FAO), which elicits the production of reduced flavin adenine dinucleotide (FADH 2 ), ultimately triggering exacerbation of LPO cascades [ 32 ]. Lipid droplets (LDs), which bud off from the cytosolic leaflet of the endoplasmic reticulum (ER) membrane, are frequently localized adjacent to mitochondria and other organelles. By sequestering damaged membrane material, LDs maintain organellar functionality during oxidative stress. On the other hand, the process of lipolysis that breaks down LDs will lead to the release of oxidized lipid species. This greatly increases their susceptibility to lipid peroxidation [ 33 ]. Therefore, from the standpoint of modulating LD metabolism, inhibiting LD formation or promoting LD degradation can abrogate their organelle-protective effects, elevate the risk of lipid peroxidation, and ultimately enhance cellular ferroptosis. Key regulators of ferroptosis In general, the molecular regulators of ferroptosis may be classified into three functional classes: negative regulators, positive regulators, and context-dependent or bidirectional regulators. Cellular metabolic and redox signalling regulators associated with ferroptotic susceptibility fall into these categories. Herein, we provide an overview of these regulatory classes and their representative molecules (Fig. 3 ). Fig. 3. Open in a new tab Key regulation of ferroptosis. This figure delineates the principal molecular framework governing ferroptosis regulation, organized into three conceptual modules. Section A summarizes the inhibitory arm of ferroptotic control, encompassing the GPX4 pathway together with the FSP1-CoQ 10 -NAD(P)H and GCH1-BH4 antioxidant axes, each contributing to the suppression of lipid peroxidation under distinct cellular contexts. Section B focuses on ferroptosis-promoting mechanisms, with BAP1-mediated regulation serving as a representative node that integrates metabolic and transcriptional inputs to potentiate ferroptotic signalling. Section C highlights the context-dependent duality of p53 and HIF-1α in ferroptosis regulation. p53 may facilitate ferroptotic death by modulating key metabolic and antioxidant pathways, yet under certain conditions, it acts protectively by enhancing cellular resilience. Likewise, HIF-1α exerts divergent effects—either restraining or amplifying ferroptotic sensitivity—through coordinated control of iron metabolism, lipid remodeling, and redox balance. KLF14: kruppel-like factor 14; ARE: antioxidant response element; Nrf2: nuclear factor E2-related factor 2; KEAP1: kelch like ECH associated protein 1; Cys: cysteine; mTORC1: Mammalian target of rapamycin complex 1; 4EBP: eukaryotic translation initiation factor 4E-binding protein; NSUN2: NOP2/Sun RNA methyltransferase 2; STUB1: C-terminus of Hsc70-interacting protein; TRAF6: tumour necrosis factor receptor-associated factor 6; PTM: post-translational modification; GPX4: glutathione peroxidase 4; NAD(P)H: nicotinamide adenine dinucleotide phosphate; FSP1: ferroptosis suppressor protein 1; CoQ 10 : Coenzyme Q 10 ; FAD: flavin adenine dinucleotide; FADH 2 : reduced flavin adenine dinucleotide; IPP: isopentenyl pyrophosphate; MVD: mevalonate diphosphate decarboxylase; GTP: guanosine triphosphate; DHNP: 7,8-dihydroneopterin 3’-phosphate; BH4: tetrahydrobiopterin; RTA: radical-trapping antioxidants; GCH1: GTP cyclohydrolase 1; BAP1: BRCA1-associated protein 1; H2A: histone 2 A; SLC7A11: solute carrier family 7 member 11; GSH: glutathione; PUFAs: polyunsaturated fatty acids; HIF-1α: hypoxia-inducible factor-1 α; ACSL4: acyl-CoA synthetase long-chain family member 4; ALOX12: arachidonate 12-lipoxygenase 12 S type; OTUD5: ovarian tumour domain-containing 5; iPLA 2 β: calcium-independent phospholipase A2β; SLC1A1: solute carrier family 1 member 1; FABP3/7: fatty acid binding proteins 3 and 7; LDH: lactate dehydrogenase Core inhibitory factors Ferroptosis is strictly regulated by three parallel complementary antioxidant defence axes, which collectively maintain redox homeostasis and inhibit lipid peroxidation. Centred on GPX4, FSP1-CoQ 10 -nicotinamide adenine dinucleotide phosphate (NAD(P)H), and GCH1-BH4, these three axes collectively form the core inhibitory network of ferroptosis. System xc − -GSH-GPX4 axis: the classical inhibitory pathway of ferroptosis System xc − -GSH-GPX4 axis: the classical inhibitory pathway of ferroptosis As the primary inhibitory pathway governing ferroptosis, GPX4 acts as a crucial molecular ‘brake’, determining cellular tolerance to lipid peroxidation [ 17 , 25 ]. The expression and activity of GPX4 are regulated through multi-tiered mechanisms, encompassing transcriptional regulation, translational control, and post-translational modifications (PTMs). These regulatory systems help maintain redox homeostasis. At the transcriptional level, nuclear factor erythroid 2-related factor 2 (NFE2L2/Nrf2) is the main activator of GPX4 transcription [ 34 ]. The presence of oxidative stress alters the structure of kelch-like ECH-associated protein 1, which induces the dissociation of attached NFE2L2/Nrf2. The released NFE2L2/Nrf2 then translocates into the nucleus to bind to the antioxidant response element (ARE) in the GPX4 promoter region, initiating transcription and thereby significantly enhancing GPX4 mRNA expression [ 35 , 36 ]. The binding of NFE2L2/Nrf2 to ARE sequences can enhance the expression of System xc − -related genes, thereby improving GSH synthesis capacity and inhibiting ferroptosis; this regulatory mechanism has been validated in acute lung injury models [ 37 ]. Conversely, certain transcription factors (such as kruppel-like factor 14) can suppress the expression of GPX4 and SLC7A11, thereby enhancing the cell’s resistance to ferroptosis [ 38 , 39 ]. Thus, decoding the dynamic effect of transcription factors, including NFE2L2/Nrf2 and KLF14 on GPX4 transcription, especially in TME, represents an key research avenue in this field. At the translational level, GPX4 is regulated by mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Cystine can activate downstream targets of the mTORC1. Cystine promotes the binding of GPX4 mRNA to ribosomes via the Rag-mTORC1-4EBP pathway, thereby leading to enhanced GPX4 translation efficiency [ 40 ]. This discovery provides a theoretical foundation for combinatorial cancer therapy using mTORC1 inhibitors combined with ferroptosis inducers. At the PTMs level, GPX4 is regulated by ubiquitin modification. For example, mechanistic studies have shown that the E3 ubiquitin ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) promotes GPX4 ubiquitination and induces ferroptosis in BC cells by reducing the stability of GPX4 [ 41 ]. As an deubiquitinating enzyme, ovarian tumour domain-containing protein 5 (OTUD5) maintains the stability of GPX4 [ 42 ]. The discovery of OTUD5 highlights the importance of deubiquitination in ferroptosis. However, its tissue-specific expression patterns, upstream regulatory signals, and potential competitive/synergistic interactions with E3 ubiquitin ligases like TRAF6 warrant future investigations. Accompanying ubiquitination, other PTMs, such as phosphorylation, succinylation and glycosylation have been shown to be involved in the regulation of GPX4 function [ 43 ]. However, their exact biochemical role in shaping ferroptotic sensitivity of tumour cells still require further investigations. In summary, the functional regulation of GPX4 exhibits an integrated, multi-layered network characteristic rather than a simple superposition of independent mechanisms. Future research will focus on elucidating the complex hierarchical molecular regulatory architecture of GPX4 and how these elements coordinate to respond to cellular activities. FSP1-CoQ 10 -NAD(P)H axis: an anti-ferroptotic pathway parallel to GPX4 Independent of the System xc⁻-GSH-GPX4 axis, the FSP1-CoQ 10 -NAD(P)H pathway functions as another key ferroptosis inhibitor. FSP1 reduces CoQ 10 to its reduced form, CoQ 10 H 2 (panthenol), which directly neutralises lipid peroxyl radicals (LOO·) in situ, thereby inhibiting the sustained activation of the ferroptosis cascade [ 18 , 20 ]. Since CoQ 10 is crucial for membrane lipid production, this process is most prominent in plasma and mitochondrial membranes. The electron donor responsible for CoQ 10 redox processes are NAD(P)H. NAD(P)H transfers electrons to flavin adenine dinucleotide (FAD), reducing the latter to FADH 2 . Afterwards, FADH 2 serves as an intermediate electron carrier by donating electrons to CoQ 10 , culminating in the reduction of CoQ 10 to CoQ 10 H 2 . Based on this mechanism, CoQ 10 scavenges electrophilic ROS and electron leakage associated with FSP1-coordinated NAD(P)H oxidation [ 21 , 44 ]. The FSP1-CoQ 10 -NAD(P)H pathway therefore constitutes an independent ferroptosis inhibitory pathway parallel to System xc − -GSH-GPX4 pathway. The combination of these two pathways prevents ferroptosis to maintain the homeostasis of the cell. Mevalonate diphosphate decarboxylase (MVD) is a key player in this pathway’s upstream regulation. Using acetyl-CoA as the first substrate, MVD generates isopentenyl pyrophosphate (IPP) through a multi-step reaction. IPP is a crucial molecule in the generation of CoQ 10 . It also facilitates the modification of selenocysteine-tRNA, which enhances resistance to ferroptosis via the FSP1-CoQ 10 -NAD(P)H pathway [ 45 ]. A recent study found that 6-hydroxy-FAD (6-OH-FAD)—an intermediate produced under FSP1-catalyzed—functions as an independent radical-trapping antioxidant (RTA) capable of directly scavenging lipid peroxidation-derived free radicals [ 44 ]. The reduction pathway of CoQ 10 does not relate to the antioxidant action of 6-OH-FAD unlike the mechanism of CoQ 10 H 2 . This finding provides a new target for tumour therapy based on ferroptosis, but its precise regulatory mechanism (production efficiency, action distance, downstream synergistic molecule, etc.) needs to be further explored deeply. It is worth noting that the regulation of FSP1 by NFE2L2/Nrf2 remains controversial, with studies indicating that FSP1 expression is not entirely controlled by NFE2L2/Nrf2 [ 46 , 47 ]. Due to differences in cell type, cancer type, or TME heterogeneity, this inconsistency in regulatory mechanisms likely indicates that the transcriptional regulatory network of FSP1 is more complicated than we know. Moving forward, researchers will need to analyse this complexity as one of the major scientific issues. GCH1-BH4 axis: synergistic effects of lipid remodelling and free radical scavenging GCH1 is the rate-limiting enzyme in BH4 biosynthesis [ 22 ]. It exerts its anti-ferroptotic effects through two interrelated mechanisms: direct radical scavenging and regulation of CoQ10 biosynthesis. First, as the molecule is a potent lipid-soluble RTA, one can see its molecular structure possessing an aromatic ring which can directly quench lipid free radicals and, thus, block lipid peroxidation cascades. Second, BH4 serves as a crucial cofactor in its own recycling process and regulates CoQ 10 biosynthesis. As such, this interplay thus forms a positive feedback loop with the FSP1 system to enhance cellular antioxidant defence capacity [ 48 ]. Research suggests that ionising radiation can reduce the levels of BH4 inside the cell and activate ROS cascades. Importantly, the activation of NFE2L2/Nrf2 can reverse BH4 deficiency and suppress ROS cascades activation by upregulating GCH1 expression [ 49 ]. Further validation is required to test if this regulatory mechanism is applicable to the TME or tumour cells. This research finding lays the basic principles which provide practical insights and research opportunities for the clinical strategy of combination radiotherapy and ferroptosis inducers for the treatment of tumours. NFE2L2/Nrf2: the primary regulatory factor of the ferroptosis suppression system NFE2L2/Nrf2, acting as a core transcriptional regulator, coordinates the expression of key factors (GPX4, FSP1, GCH1) within the aforementioned three inhibitory pathways. By activating the transcription of these ferroptosis-suppressing factors, NFE2L2/Nrf2 enhances cellular resistance to ferroptosis [ 34 – 37 , 49 ]. This indicates that NFE2L2/Nrf2 is an critical component of the ferroptosis network. Thus, inducing ferroptosis by inhibiting NFE2L2/Nrf2 in tumour cells holds great clinical and practical significance. In BC, taraxerol effectively induces ferroptosis in BC cells by targeting NFE2L2/Nrf2 associated with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mTOR signalling pathway [ 50 ]. Moreover, hydroxytyrosol in colorectal cancer (CRC) has been shown to specifically target NFE2L2/Nrf2 signalling to inhibit the expression of the functional subunit SLC7A11 of System xc − and GPX4, and the concentration of free cellular iron, ultimately inducing ferroptosis in tumour cells synergistically [ 51 ]. To summarize, the NFE2L2/Nrf2 is an important target for various upstream regulatory factors that inhibit ferroptosis. It also serves as a shared target mediating ferroptosis resistance. In addition, NFE2L2/Nrf2 can be targeted for anti-tumour treatment by inducing ferroptosis as it can regulate the activity of a number of ferroptosis inhibiting targets. This knowledge will provide valuable guidance for the future development of targeted drugs and rational design of combinatorial therapies. Core promoting factors The promotion of ferroptosis is mediated by p53 and BRCA1-Associated Protein 1 (BAP1), primarily acting through two distinct mechanisms: either by impairing cellular antioxidant defences or by amplifying lipid peroxidation signalling. p53: a context-dependent dual regulator of ferroptosis As a classic tumour suppressor gene, p53 regulates ferroptosis through both transcription-dependent and transcription-independent mechanisms, exhibiting pronounced bidirectional regulatory properties. Its pro-ferroptotic actions include: inhibiting ferroptosis defence pathways (e.g., SLC7A11, OTUD5) and enhancing lipid peroxidation reactions (e.g., ACSL4, arachidonate 12-lipoxygenase 12S type [ALOX12]). First, p53 directly suppresses the promoter activity of SLC7A11 while downregulating OTUD5, a deubiquitinating enzyme. Ferroptosis is promoted by this dual inhibition of ferroptosis defence pathways [ 5 , 42 ]. The upregulation of ACSL4 expression by p53 ensures adequate levels of PUFAs in membrane PLs to drive lipid peroxidation. At the same time, p53 induces the expression of ALOX12, which catalyses the generation of ferroptosis-specific LPO signals; these effects collectively trigger ferroptosis [ 52 ]. In contrast to the above, p53 may also induce cells to exert anti-ferroptotic effects by regulating lipid metabolism. Research indicates that p53 reduces cell sensitivity to ferroptosis induced by System xc − inhibitors, e.g. erastin [ 5 ]. Moreover, mechanistic studies further reveal that p53 exerts this effect through the induction of calcium-independent phospholipase A2β (iPLA2β) [ 53 ]. In lipid metabolism, iPLA2β increases the capability of tumour cells to inhibit ferroptosis through a reduction of oxidized PLs [ 54 ]. In summary, p53 acts as a typical double-edged sword regulator for ferroptosis regulation. This seemingly contradictory research outcome actually reflects the pervasive limitations of ‘dualistic’ thinking in current studies. Such conflicting results further substantiate that p53’s regulation of ferroptosis is not a simple matter of promotion or inhibition, but rather a highly context-dependent and dynamic process. Specifically, p53’s pro-ferroptotic or anti-ferroptotic effects are strongly contingent upon cell type, stress signal type, p53 mutation status, and the expression levels of specific transcriptional co-activators. From a methodological perspective, variations in ferroptosis inducers, in vitro models, and the cross-over of cell death pathways may significantly influence research outcomes. In summary, the p53-mediated ferroptosis regulatory network underscores the urgent need for more in-depth and consistent mechanistic studies centred on p53 and ferroptosis. BAP1: epigenetic and post-translational regulation of ferroptosis BAP1, as a key tumour suppressor gene within the ubiquitin C-terminal hydrolase (UCH) family, regulates ferroptosis through epigenetic modifications and protein stability control [ 55 ]. Its mechanism of action involves: BAP1 inhibits SLC7A11 transcription by deubiquitinating histone 2 A (H2A), whilst simultaneously prolonging the half-life of FOXO3a through deubiquitination. To begin with, BAP1 suppresses the transcriptional activity of SLC7A11, achieved via deubiquitination of H2A. In turn, this leads to reduced cystine uptake in cells and GSH synthesis levels. Ultimately, this promotes ferroptosis [ 56 ]. Recent molecular studies have revealed that BAP1’s deubiquitinating activity specifically targets the monoubiquitination of lysine 119 on histone H2A [ 57 ]. This result gives important information about how BAP1 regulates SLC7A11 transcription through epigenetics. Moreover, other studies have demonstrated BAP1 directly binds to forkhead box protein O3a (FOXO3a) protein via its UCH domains, thereby removing its K48-linked ubiquitin chain from FOXO3a. Considering that K48-linked ubiquitin chains are well-known for signalling proteasomal degradation of proteins, the de-ubiquitinating effect of BAP1 greatly prolongs the half-life of FOXO3a, allowing it to continuously activate expression of downstream ferroptosis- associated target genes [ 58 ]. This finding enhances our understanding of how BAP1 actually enhances ferroptosis at the molecular level. Furthermore, it can be a new target for the design of drugs to interfere with ferroptosis from the perspective of protein stability regulation. HIF-1α HIF-1α regulates ferroptosis in a context-dependent manner. In controlling different downstream targets, HIF-1α can exert opposing effects on ferroptosis, promoting ferroptosis in tumour cells, but preventing it in cells of the immune system [ 59 ]. Under hypoxic conditions, HIF-1α causes solute carrier family 1 member 1 (SLC1A1) to express, allowing for glutamate uptake. This mechanism enhances extracellular cystine uptake via the cystine-glutamate antiporter, thereby encouraging the synthesis of GSH and enhancing activity of GPX4, inhibiting ferroptosis [ 12 ]. HIF-1α can also upregulate the expression of fatty acid binding proteins 3 and 7 (FABP3/7). This proteins promote LDs formation by enhancing fatty acid uptake and lipid storage, thus preventing ferroptosis [ 13 ]. HIF-1α is another mediator of the transcriptional activation of lactate dehydrogenase (LDH). This activation leads to intracellular accumulation of lactate that forms a pH-dependent ferroptosis resistance pathway parallel to the classical SLC7A11 and FSP1 systems [ 12 ]. Notably, under the same hypoxic condition, HIF-1α can act differently through different pathways. It increases the expression of TfR1, which increases iron entry into cells and induces ferroptosis via iron metabolism imbalance [ 60 ]. Thus, it is potentially important to inhibit hypoxic signalling pathways in anti-cancer therapy considering the HIF-1α-mediated ferroptosis regulation through multiple pathways. However, the dual role of HIF-1α complicates the implementation of this targeting strategy. It is worth noting that the dual role of HIF-1α highlights significant methodological limitations in existing research. Firstly, most studies rely on in vitro hypoxia models, yet these conditions struggle to authentically replicate the dynamic oxygen gradients within the TME, potentially exaggerating or obscuring specific effects of HIF-1α. Secondly, criteria for defining ferroptosis vary across studies; some works rely solely on lipid peroxidation or cell mortality changes, lacking systematic validation of GPX4 activity or iron metabolic flux. Finally, HIF-1α regulation often occurs indirectly through transcriptional networks, yet many studies focus solely on single targets (e.g., SLC7A11 or TfR1), overlooking the combined effects of parallel multi-pathway regulation and thus yielding partial conclusions. Furthermore, variations in HIF-1α activation mechanisms across different experimental systems have not been fully accounted for, further diminishing the comparability of findings. Consequently, akin to p53, HIF-1α’s dual role in ferroptosis reflects context-dependent regulation. Future work requires systematic analysis of priority and counterbalancing relationships among distinct HIF-1α downstream pathways within models approximating physiological conditions. This should integrate single-cell metabolic profiling with chronological intervention strategies, facilitating precise targeting of HIF-1α for ferroptosis regulation. Ferroptosis and other forms of cell death Ferroptosis and apoptosis Apoptosis is a genetically regulated form of programmed cell death (PCD) that plays a critical role in maintaining organismal homeostasis [ 61 ]. Although ferroptosis and apoptosis exhibit distinct morphological characteristics and molecular mechanisms, a growing body of research indicates a close relationship between the two. Particularly during endoplasmic reticulum stress, redox imbalance, and drug responses, these two forms of cell death can undergo mutual conversion or occur synergistically. Under ER stress conditions, ferroptosis-induced lipid peroxidation activates the PERK–eIF2α–ATF4–CHOP pathway, thereby upregulating pro-apoptotic factors such as PUMA and driving a shift from ferroptosis to mitochondrial-dependent apoptosis [ 62 ]. This is exemplified by the action of ferroptosis inducers, which trigger ER stress to promote the CHOP-mediated, p53-dependent upregulation of apoptotic regulators like PUMAs [ 63 ]. Molecular studies reveal BAK, a member of the B-cell lymphoma 2 (BCL-2) family, as a pivotal link between ferroptosis and apoptosis. Co-treatment with erastin and TRAIL enhances BAK oligomerisation and mitochondrial aggregation, disrupting mitochondrial membrane potential to activate caspases and induce apoptosis [ 64 ]. Furthermore, in triple-negative breast cancer (TNBC), the key ferroptosis inhibitor GPX4 was found to promote mitochondrial-mediated apoptosis via upregulation of early growth response 1, revealing GPX4/EGR1 as a potential target for combined ferroptosis-apoptosis therapy [ 65 ]. Within the oncotherapy context, the combined induction of ferroptosis and apoptosis in tumour cells has been demonstrated to effectively eliminate acute myeloid leukaemia cells [ 66 ]. Furthermore, targeted inhibition of ferroptosis and apoptosis signalling pathways holds promise for overcoming chemotherapy resistance in breast cancer [ 67 ]. Interestingly, Salvia miltiorrhiza, a traditional Chinese medicine for lung cancer, has been revealed to kill lung cancer cells by inducing ferroptosis and apoptosis [ 68 ]. However, its precise mechanism remains to be elucidated. At the molecular regulatory level, long non-coding RNA (lncRNA) have been demonstrated to sequester p53 within the nucleus, triggering ferroptosis and apoptosis in tumour cells [ 69 ]. This suggests the lncRNA–p53 axis represents a crucial molecular mechanism linking and coordinating these two forms of cell death. Consequently, the combined induction of ferroptosis and apoptosis is considered a promising anti-tumour strategy [ 70 ]. Moreover, with advances in computational bioscience, bioinformatics and deep learning-based models for identifying cell death phenotypes have been employed to distinguish ferroptosis from apoptosis, predict drug-induced cell death types, and identify biomarkers for ferroptosis and apoptosis. These approaches provide novel technical tools for precisely regulating both death pathways and designing combined therapeutic regimens [ 71 , 72 ]. In the future, computational bioscience holds promise for discovering and validating further interactive mechanisms between ferroptosis and apoptosis, thereby providing multiple intervention targets and therapeutic strategies for clinical cancer treatment. The mechanisms underlying the crosstalk between ferroptosis and other cell death modalities are illustrated in Fig. 4 . Fig. 4. Open in a new tab Crosstalk between ferroptosis and other cell death modalities. This figure depicts the intrinsic interplay between ferroptosis and other RCD pathways, including necroptosis ( A ), apoptosis ( B ), autophagy ( C ), cuproptosis ( D ), and pyroptosis ( E ). Ferroptosis can intersect functionally with these modalities, and in certain contexts, act upstream to trigger apoptotic, necroptotic, or pyroptotic cascades. Autophagy occupies a particularly complex position in this network: selective autophagic processes such as ferritinophagy, lipophagy, and clockophagy promote ferroptotic sensitivity by mobilizing intracellular Fe 2+ , enriching polyunsaturated lipid substrates, or diminishing antioxidant reserves. Conversely, Reticulophagy and Lysophagy inhibit ferroptosis by alleviating ER stress and clearing damaged lysosomes, respectively. Cuproptosis also exhibits dual effects on ferroptosis: Cu 2+ can inhibit ferroptosis by inducing GPX4 expression in an FDX1-dependent manner, while simultaneously promoting ferroptosis by increasing ROS. mPTP: mitochondrial permeability transition pore; ROS: reactive oxygen species; GPX4: glutathione peroxidase 4; BCL-2: B-cell lymphoma 2; NCOA4: nuclear receptor coactivator 4; PUFAs: polyunsaturated fatty acids; HIF-1α: hypoxia-inducible factor-1 α; BMAL1: basic helix-loop-helix ARNT-like 1; ER: endoplasmic reticulum; RETREG1: reticulophagy regulator 1; TAX1BP1: tax1 binding protein 1; FDX1: ferredoxin 1; GSDMD: gasdermin D Ferroptosis and necroptosis Necroptosis is a type of PCD triggered by the activation of receptor-interacting protein kinase 1 (RIPK1), followed by the phosphorylation of RIPK3 and mixed lineage kinase domain-like protein [ 61 ]. In the case of ischemic stroke, the process of ferroptosis can cause the buildup of ROS. Excessive ROS causes ER stress and a malfunction of the mitochondria. This, in turn, promotes the opening of the mitochondrial permeability transition pore (mPTP). This process ultimately leads to mitochondrial energy metabolism disorders, organelle and cell membrane swelling, and subsequent necroptosis [ 73 ]. Moreover, iron overload may also cause mPTP opening and further promotes RIPK1 phosphorylation and necroptosis [ 73 ]. The process of ferroptosis promoting necroptosis suggests it may be a good entry point for application of dual-induction cell death strategy-ferroptosis and necroptosis activation for anti-tumour therapy. This is not the case in oncology. More research needs to be done on the crosstalk and intrinsic regulatory mechanisms between ferroptosis and necroptosis. Further extensive studies must clarify and enhance them. Ferroptosis and autophagy Autophagy is a basic rate-limiting process for maintaining physiological cell homeostasis through the selective degradation and recycling of intracellular components. Although they exhibit an inherent reciprocal relationship, the precise regulatory crosstalk between autophagy and ferroptosis depends primarily on the specific subset of targeted autophagy activated and the overall cellular context, particularly in the context of pro- and anti-ferroptotic cell death. Indeed, genetic silencing or ablation of cardinal autophagy genes including autophagy-related protein (ATG)5 and ATG7 is reported to inhibit erastin lipid peroxidation activity and consequently minimizes ferroptotic cell demise, while NCOA4-regulated autophagic degradation of ferritin results in increased amounts of Fe 2+ , thereby favouring ROS production and subsequent ferroptosis [ 74 ]. While other forms of this “mechanistically-autopro-inducible” ferroptotic mode of cell death represent an important subset of ferroptosis driven by substrate/organelle overload, the existing autophagy-dependent ferroptosis is collectively termed as autophagy-dependent ferroptosis. Over the last decade, as our know-how on both autophagy and ferroptosis has matured, we arrived at a general consensus on the relationship between both modalities [ 75 ]: specific types of autophagy (e.g., ferritinophagy, lipophagy [ 76 ], and clockophagy [ 77 ]) can initiate or execute ferroptosis by selectively degrading anti-ferroptotic proteins or organelles. Conversely, other forms of selective autophagy (e.g., reticulophagy [ 78 ] and lysophagy [ 79 ]) can enhance the cell’s defensive capacity against ferroptosis. Pro-ferroptotic forms of autophagy may potently promote ferroptosis via distinct and mechanistically differentiated pathways; depending on the type of engaged autophagic process, their patterns of regulation are predetermined. Of these, ferritinophagy, mediated by the selective cargo binding protein NCOA4, drives ferritin toward lysosomal degradation and releases Fe 2+ . This released Fe 2+ drives the production of potentially damage-causing ROS via the Fenton reaction pathway, increasing lipid peroxidation and leading to ferroptotic cell death [ 74 , 80 ]. In pancreatic cancer (PC) models, Erastin treatment significantly enhances NCOA4-mediated ferritinophagy, sensitizing the tumour cells to ferroptosis [ 74 ]. As another crucial pro-ferroptotic pathway, lipophagy coordinates the autophagic turnover of LDs and facilitates the hydrolysis that releases PUFAs. The substitution of PUFAs for other lipids enhances lipid peroxidation to augment ferroptotic injury [ 33 ], notably progesterone receptor membrane component 1 (PGRMC1) has been found to upregulate lipophagy thereby making paclitaxel-resistant tumour persister cells highly vulnerable to Erastin-induced ferroptosis [ 81 ]. As the third mechanism linking autophagy to ferroptosis, clockophagy converges autophagic degradation with circadian rhythms. The basic helix-loop-helix ARNT-like 1 (ARNTL/BMAL1) protein is a transcription factor that drives rhythmic gene expression. During clockophagy, the selective autophagy receptor sequestosome-1 (SQSTM1/p62) mediates ARNTL/BMAL1 degradation, lifting ARNTL/BMAL1’s transcriptional repression of prolyl hydroxylase (PHD)1 and thereby increasing PHD1 expression. Elevated PHD1 promotes HIF-1α destabilization; the consequent reduction in HIF-1α weakens cellular antioxidant defenses and creates a permissive environment for lipid peroxidation [ 77 , 82 ]. Similarly, in HCC models, ubiquitin-specific peptidase 2 can preempt SQSTM1/p62-selective clockophagy targeting ARNTL/BMAL1, while its pharmacological suppression reinstates this process and leads to a dramatic upregulating of sensitivity to ferroptosis in HCC cell [ 83 ]. Taken together, ferritinophagy, lipophagy, and clockophagy coalesce as distinct convergent autophagic processes that accelerated ferroptotic cell death via independent molecular mechanisms and serve as valuable cues for fathoming the autophagy-ferroptosis crosstalk in order to direct the rational design of future ferroptosis-targeting therapeutic strategies. Unlike its ferocity-driven counterpart, anti-ferroptotic autophagy regulates ferroptotic cell death with distinct and highly refined means. Most exemplary is reticulophagy, a selective autophagy mediated by the ER-resident receptor reticulophagy regulator 1 (RETREG1/FAM134B), which binds to autophagy modulators including Microtubule-associated protein 1 A/1B-light chain 3 (LC3) and γ-aminobutyric acid type A receptor–associated protein to promote ER turnover via the autophagic pathway [ 84 ]. By attenuating ER stress and load and thereby reducing ROS build‐up, reticulophagy has previously been shown to be a protective ferroptosis signalling‐attenuating mechanism. Indeed, it was recently reported that sorafenib (SRF), a multi‐kinase inhibitor that modulates ferroptosis in a context‐dependent manner, activates RETREG1/FAM134B‐mediated reticulophagy, thereby suppressing ferroptosis in HCC cells [ 85 ]. A second key process is lysophagy, a selective clearance of damaged lysosomes to limit lysosomal Fe 2+ release, as well as limit oxidative stress against ferroptotic injury [ 15 ]. However, revelations establish a signalling landscape with the TANK binding kinase 1 (TBK1)-F‐box protein 3 (FBXO3)-transmembrane protein 192 (TMEM192)-Tax1-binding protein 1 (TAX1BP1) axis as the master switch of lysophagy. When lysosomal damage occurs, TBK1 is activated, thereby phosphorylates FBXO3 to promote TMEM192 ubiquitination at the lysosomal membrane. TAX1BP1 subsequently recognizes ubiquitinated TMEM192 to mediate selective clearance of damaged lysosomes by the autophagic pathway [ 86 ]. Moreover, lysosomal rupture can be triggered by mechanical forces such as cellular compression, leading to TAX1BP1 recruitment, inducing lysophagy, and mitigating ferroptotic injury during intervertebral disc degeneration [ 87 ]. In summary, although new insights are emerging, the exact role of lysophagy in regulating ferroptosis in tumour cells remain to be investigated. The in-depth understanding of the interplay between these anti-ferroptotic autophagy mechanisms, tumour metabolism, and adaptive stress response [ 88 ] is critical for advancing translational biology. The combined pro-versus anti-ferroptotic forms of autophagy define an intricate regulatory network that which determines cellular responsiveness to ferroptosis. Targeting this autophagy–ferroptotic axis offers a valuable therapeutic option for ferroptosis–associated pathologies, including malignancies [ 89 ]. Beyond these pathways, research on the combined effects of Mdivi-1 and indomethacin on GC cells indicates that Mdivi-1 (Mitochondrial division inhibitor 1) suppresses the mitochondrial fission function mediated by dynamin-related protein 1 (Drp1). Indomethacin disrupts the equilibrium between mitochondrial fission and fusion in GC cells, downregulates the expression of mitochondrial autophagy-regulating protein PINK1, impedes the autophagic degradation of damaged mitochondria, and induces a pathological mitochondrial state. This subsequently activates endogenous apoptotic pathways, upregulates apoptotic proteins (such as Bax, Puma, and Noxa), ultimately inducing GC cell death [ 90 ]. This study demonstrates that mitochondrial dysfunction caused by PINK1 can be exploited as a therapeutic target for cancer [ 90 ]. Given the close association between ferroptosis and mitochondria, cell death mechanisms triggered by mitochondrial dysfunction may also contribute to ferroptosis, thereby establishing a conceptual link between mitochondrial homeostasis maintenance and ferroptosis susceptibility in cancer. Consequently, future research into mitochondrial quality control via mitophagy holds promise for transcending conventional notions of autophagy, potentially emerging as a key determinant of ferroptosis susceptibility. Ferroptosis and pyroptosis Pyroptosis is a lytic program of PCD that is catalyzed by Gasdermin (GSDM) family proteins. During pyroptosis, cytoplasmic swelling, disruption of cell membrane integrity, and subsequent release of pro-inflammatory mediators occur, leading to cell death [ 91 ]. Intriguingly, recent studies have demonstrated that ferroptosis can also serve as an upstream promoter of pyroptosis, highlighting the mechanistic interaction between these two RCD pathways. More specifically, lipid peroxidation, the canonical process of ferroptosis, is known to be a stimulus of caspase-11. After activation, caspase-11 acts as a catalyst that cleaves GSDM family proteins to generate the N-terminal pore-forming fragments of GSDMs, subsequently leading to initiation and execution of pyroptotic cell death via a phospholipase Cγ1-dependent signaling cascade [ 92 , 93 ]. This mechanism implicates lipid peroxidation as a key biochemical node where the two processes (where ferroptosis and pyroptosis interface) interface. A recent discovery has suggested the involvement of another pathway (TOM20-Bax-caspase-GSDME axis) as the main route through which iron-mediated ferroptosis can activate secondary pyroptosis. Ferroptotic stress induced ROS promotes oxidative modification and oligomerization of mitochondrial translocase TOM20. The modified TOM20 recruits in recruitment of the pro-apoptotic protein Bax, into the mitochondrial membrane to mediate the release of cytochrome c into the cytosol to activate the processing of caspase-3. Once activated, caspase-3 catalyses the cleavage of GSDME, releasing its active N-terminal domain and triggering pyroptosis [ 94 ]. In summary, downstream ferroptosis-induced downstream pyroptosis has been demonstrated; however, whether pyroptosis can reversely interfere with ferroptotic signalling, is another unresolved question that requires further rigorous investigation. Nevertheless, there is increasing evidence that the interconversion between both death modalities can be harnessed therapeutically. For instance, human UCNP-Cro/FA nanoparticles loaded with an NIR induce ferroptosis via hydroxyl radical (·OH) action mediated by endogenous iron, preceding lysosomal membrane permeabilization which triggers activation of caspase-1/GSDMD-dependent pyroptotic pathway, ultimately leading to robust pyroptotic cell death [ 95 ]. Taken together, these results provide both mechanistic as well as experimental evidence to support the development of integrated anti-tumour strategies that leverage the cooperation of these two death processes of ferroptosis and pyroptosis could be developed. Ferroptosis and cuproptosis Copper-mediated cell death, or cuproptosis, which was first characterized in 2022, is driven by Cu 2+ accumulation closely associated with mitochondrial respiratory metabolism. Mechanistically, Cu 2+ directly targets lipoylated forms via the tricarboxylic acid cycle, especially dihydrolipoamide dehydrogenase, leading to abnormal lipoylated proteins, destabilization of proteotoxic intracellular iron-sulfur (Fe-S) cluster-containing enzymes, and subsequent proteotoxic stress and cell death [ 96 – 98 ]. Recent clear evidence implicates the Fe-S cluster protein ferredoxin 1 (FDX1) in this mechanism. FDX1 can reduce Cu 2+ to the reactive Cu + forms to enhancing oxidative stress and ROS-dependent cytotoxicity [ 99 ]. These findings indicate that FDX1 may serve as a cell death molecular interface between two oxidative cell death kill systems that share similar regulation. Recent reports have further discovered a direct interface between copper homeostasis and ferroptotic signalling. Specifically, Cu 2+ can target the lipid peroxidation suppressor GPX4 and facilitate its ubiquitination and aggregation. The autophagy receptor TAX1BP1 then mediates GPX4 degradation that which further boosts the execution of ferroptosis [ 100 ]. Despite cuproptosis and ferroptosis converging towards similar biochemical fingerprints, such as ROS overaccumulation, mitochondrial dysfunction, and metabolic stress, understanding their shared signalling shared signalling circuits and crosstalk is necessary to unravel how these metal ion-catalyzed death mechanisms can be repurposed for therapeutics. Certainly, these insights will shape rational approaches for designing the combined anti-tumour strategies that leverage the synergistic potential of ferroptosis and cuproptosis. To conclude, ferroptosis exemplifies a multifaceted mechanistic crosstalk with other RCD pathways. Consequently, these differentiated modalities increasingly have come to be treated as potential co-adjuvants in orchestrated tumour cell killing. With mounting evidence, ferroptosis no longer functions in isolation and instead forms part of an interconnected network of immune cell death programmes [ 101 ], whereby various death programmes can potentially converge for optimal anti-tumour efficacy. From this perspective, however, current knowledge of this crosstalk is somewhat fragmentary, and extensive refinement, both methodological and conceptual, appears to be imperative. Such a refinement needs to focus on developing novel analytical tools specifically designed for parsing RCD mechanisms [ 102 ]. Furthermore, establishing a complete spatiotemporal overview of the influence of different RCD modalities on ferroptosis will prove invaluable in shaping a holistic framework surrounding RCD and therapeutic application [ 103 ]. Temporal specificity of ferroptosis Temporal dynamics of ferroptosis In terms of time, the course of ferroptosis can be relatively divided into three stages, including initiation, execution, and finishing stage [ 3 , 104 ]. These stages have specific molecular reactions and cellular procedures, which present the whole beaming process of ferroptosis. A figure (Fig. 5 ) illustrates the dynamic transitions between them. Fig. 5. Open in a new tab Temporal dynamics of ferroptosis. This figure delineates the stepwise progression of ferroptosis, highlighting its molecular framework across three interconnected phases. In the initiation phase ( A ), inhibition of System xc⁻ limits cystine uptake, resulting in GSH depletion and heightened redox stress. The CTH provides only partial metabolic compensation, while regulatory factors such as p53 and NFE2L2/Nrf2 modulate this process in opposite directions. During this stage, the canonical System xc − -GSH-GPX4 antioxidant axis becomes destabilized, and auxiliary antioxidant systems-including FSP1-CoQ 10 and DHODH-begin to adjust dynamically. Meanwhile, aberrant iron metabolism amplifies cellular vulnerability through iron accumulation and Fenton-driven oxidative stress. The execution phase ( B ) centres on the enzymatic incorporation of PUFAs into PUFA–PE via ACSL4, forming the lipid substrates for peroxidation. Lipid peroxidation proceeds through a chain reaction of initiation, propagation, and termination, catalysed by ALOXs and sustained by iron-dependent Fenton chemistry. Multiple organelles-the ER, mitochondria, lysosomes, and Golgi apparatus-coordinate during this stage to shape the ferroptotic cascade. Antioxidants such as GPX4, CoQ 10 , BH4, and Vit E serve as negative regulators, mitigating the propagation of lipid damage. In the terminal phase ( C ), plasma membrane integrity is compromised by the formation and expansion of lipid nanopores, culminating in membrane rupture. The ESCRT-III complex acts as a compensatory mechanism, orchestrating membrane repair to restrain excessive cellular disruption. Meanwhile, oxidized lipids are released via exocytic vesicles and spread among cell populations in a wave-like manner. Vit E: vitamin E; Nrf2: nuclear factor E2-related factor 2; Cys: cysteine; GSH: glutathione; PUFAs: polyunsaturated fatty acids; ALOXs: arachidonate lipoxygenases; L·: lipid radical; LOO: lipid peroxyl radical; LOOH: lipid hydroperoxide; 4-HNE: 4-hydroxynonenal; MDA: Malondialdehyde; LPCAT3: lysophosphatidylcholine acyltransferase 3; POR: cytochrome P450 reductase; CYB5R1: cytochrome b5 reductase; PE: phosphatidylethanolamine; GPX4: glutathione peroxidase 4; CoQ 10 : Coenzyme Q 10 ; BH4: tetrahydrobiopterin; ER: endoplasmic reticulum; EMCS: ER-mitochondria contact sites; FINO2: (5α,8α)-8-(1,1-dimethylethyl)-3-methyl-1,2-dioxaspiro(4,5)decane-3-ethanol Initiation stage of ferroptosis The initiation of ferroptosis is driven by the convergence of three pivotal events: redox imbalance induced by cystein deficiency, adaptive remodelling of the antioxidant defence network, and iron overload. Collectively, these events foster a cellular environment conducive to the occurrence of lipid peroxidation. Cystine deprivation and enhanced transsulfuration pathway By inhibiting SLC7A11/SLC3A2-mediated systemic cystine uptake, cystine depletion occurs and GSH synthesis is blocked, constituting the initial trigger for ferroptosis. When confronted with severe cystine deficiency, cells upregulate the transsulfuration pathway to convert homocysteine into cystine. Specifically, the System xc − cystine/glutamate antiporter is an integral part of maintaining cellular redox equilibrium by exchanging extracellular cystine via a 1:1 diffusional ratio. Importantly, after entry into the cell, cystine is reduced to Cys, a stable intermediate of GSH biosynthesis and essential for intracellular redox balance [ 23 , 24 , 105 ]. Disturbances of the transporter via inhibition of core subunits SLC7A11 or SLC3A2 disrupt cystine uptake, resulting in cystine depletion, abrogation of GSH biosynthesis, and thereby instigating permissive platforms for ferroptotic cell death [ 4 , 5 ]. Severe cystine deficiency enables cells to shift to adaptive state by upregulating a compensatory metabolic pathway-the transsulfuration cascade [ 106 ]; the transsulfuration pathway is a branch of methionine metabolism that converts homocysteine to Cys through the simultaneous activity of cystathionine β-synthase and cystathionine γ-lyase (CTH) [ 107 ], which replenishes intracellular Cys reserves, reinstates GSH synthesis, and imparts resistance to ferroptotic insults. Importantly, the insensitivity of the transsulfuration pathway to inhibition enhances its potential as a therapeutic target for combating ferroptosis, which has been demonstrated in a variety of cancer types, Non-small cell lung cancer (NSCLC) [ 108 ], melanoma [ 109 ], and glioblastoma (GBM) [ 110 ], emphasizing the dynamic flexibility of metabolic networks in ferroptotic regulation time, and indicating that therapeutics targeting Cys metabolism may rationally and effectively explore the means to exploit ferroptotic susceptibility in cancer. Rewiring of the antioxidant defence network To counteract GSH depletion, cells activate alternative antioxidant pathways independent of the System xc⁻-GSH-GPX4 axis, including the FSP1-CoQ 10 -NAD(P)H, GCH1-BH4, and dihydroorotate dehydrogenase (DHODH)-CoQ10 systems. These pathways act synergistically to inhibit lipid peroxidation and delay the onset of ferroptosis. In the System xc − -GSH-GPX4 antioxidant network, GPX4 plays a role as a critically important enzyme-protective mechanism against ferroptosis. Through its reaction with reduced GSH as an electron donor, GPX4 transforms lethal PLOOHs into their benign counterparts PLOHs to prevent membrane rupture and maintain redox balance [ 17 ]. The regulation of GPX4’s expression and activity occurs at multiple levels, such as transcriptional, translational, and even PTMs, reflecting its crucial role at the center of this ferroptotic safeguard. Should GPX4 activity falter, cells will effectively make up for this deficit by utilizing other parallel regulatory antioxidant pathways, which can operate independently from the System xc − -GSH-GPX4 axis. Among the group of antioxidant systems regulated by GPX4, FSP1-CoQ 10 -NAD (P) Hand GCH1-BH4 provide an effective redox defence not only to suppress lipid peroxidation rate—but also a delay to ferroptosis’ onset [ 18 , 20 , 22 ]. Together, these mechanisms constitute a multi-layered and adaptive antioxidant network to ensure cellular survival under oxidative challenges. And in mitochondria, there is yet another safeguarding mechanism under work. Due to its mitochondrial localization, DHODH exerts its antioxidative role via catalysing the activation of CoQ 10 to its radical- scavenging antioxidant form, CoQ 10 H 2 . In this way, DHODH manages to suppress mitochondrial inner membrane lipid peroxidation control and operates away from GPX4’s scope, widening the potential modulator target pool for ferroptosis [ 111 ]. Interestingly enough, recent research reveals that LDHB [ 112 ] and mitochondrial respiratory chain complex Ⅰ (MCⅠ) [ 113 ] also act as antioxidants to attenuate mitochondria-dependent ferroptosis by modulating the CoQ 10 /CoQ 10 H 2 redox balance. Most interestingly, the beneficial impact of MCⅠ is paralleled with that of both GPX4 and DHODH and stands out exceedingly more prominently when the cellular expression level of GPX4 is simultaneously downregulated. Taken in concert, the aforementioned findings elucidate the intricate redundancy and plasticity available in the cellular antioxidant framework-the simultaneous coexistence of multiple partially overlapping defence pathways not only highlights ferroptosis control’s evolutionary significances-but also constitutes a theoretical backdrop to multi-target therapeutic strategies to involve selective disruption in antioxidant defence by enhancing ferroptotic demise in tumour cells. Iron overload: a synergistic initiator of ferroptosis Iron metabolism disorders, including enhanced iron uptake (upregulation of transferrin receptor 1), reduced iron efflux (downregulation of FPN), and increased ferritin degradation, may all lead to iron overload and enlargement of the LIP compartment (by upregulation of DMT1). Within the enlarged LIP, increased Fe 2+ catalyses Fenton reactions, generating ROS that further exacerbate redox imbalance [ 29 , 74 , 80 , 114 , 115 ]. Interestingly, SLC7A11 was identify as a critical hub in iron overload–mediated ferroptosis [ 116 ]. This highlights that the determinants of the ferroptosis molecularly are not in isolation of each other but are instead parts of a highly interwoven and coordinated molecular network. Taken together, the results indicate that, at the initiation stage of ferroptosis, the combined depletion of cystine, transsulfuration pathway activation and reconfiguration of the antioxidant defence network, and iron overload jointly control key regulatory cascades controlling ferroptotic susceptibility. The crosstalk of these metabolic and redox disruptions creates a cellular environment that propels the onset of lipid peroxidation chain reactions and facilitates subsequent changes in organelle integrity and function at the execution stage of ferroptosis. Execution stage of ferroptosis Lipid substrate generation and lipid peroxidation chain reactions The enzymatic transformation of PUFA to PUFA-PE catalysed by ACSL4 and LPCAT3 yields key substrates for the lipid peroxidation chain reactions [ 30 ]. Lipid peroxidation proceeds through three consecutive, albeit mechanistically distinct, sequentially dependent steps: initiation, propagation, and termination [ 15 ]. In the initiation phase, the Fe 2+ present in the intracellular LIP reacts with H 2 O 2 via the Fenton reaction to generate the highly reactive ·OH. Because of their strong oxidizing power, all ·OH species abstract hydrogen atoms from bis-allylic positions of PUFA chains and yield lipid radicals (L·) [ 15 ]. Additionally, cytochrome P450 reductase and cytochrome b5 reductase facilitate the transfer of electrons from NAD(P)H to molecular oxygen, generating superoxide anions (O 2 · − ). These superoxide anions subsequently undergo dismutation to form H 2 O 2 , which further reacts with Fe 2+ to produce ·OH, thereby initiating lipid peroxidation chain reactions [ 117 ]. In the propagation phase, L· then reacts rapidly with O 2 and generates LOO·. These LOO· species abstract hydrogen atoms from moieties adjacent to PUFA molecules to form novel L· and lipid hydroperoxides (LOOH), thereby perpetuating the peroxidation of propagation autocatalytically [ 15 , 118 ]. This process is coupled with the buildup of vast amounts of oxidized PLs in the membrane bilayer. Simultaneously, the cleavage of peroxidized lipids leads to the formation of electrophilic aldehydes like 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) that easily form covalent adducts with Cys residues on membrane-associated proteins, which impede protein function and translate into pro-apoptotic or pro-ferroptotic signalling pathways [ 119 ]. The nonheme iron oxygenases, namely members of the family of arachidonate lipoxygenases, include that arachidonate 3-lipoxygenase, ara-chidioneate 5-lipoxygenase, ALOX12, arachidonate 12-lipoxygenase 12R type, arachchydrone 15-lipoxygenase(ALOX15) and arachidonate 15-lipoxygenases type B can directly oxidize membrane PUFAs to generate LOOH to fuel the propagation process of lipid peroxidation [ 15 , 120 ]. Lastly, the termination phase sees the action of antioxidant systems quenching L· propagation. Antioxidants, whether enzymatic such as GPX4, CoQ 10 , and BH4 or non-enzymatic, counter the oxidant effects of LOO· by completely different redox mechanisms, thereby preventing prolonged membrane injury and further damage. Vitamin E also hydrogenates LOO· to form stabilized vitamin E radicals that efficiently shut down the lipid peroxidation chain reaction [ 15 ]. Disruption or inhibition of the antioxidant defence leads to uncontrolled accumulation of LPO and subsequently causes widespread oxidative damage to the cellular compartments such as the ER and mitochondria. This cascade propels cells to the terminal phase of ferroptosis, which ultimately leads to plasma membrane rupture and eventual cell death. Synergistic roles of organelles Previously, mitochondria have been discovered to be the major mediators of ferroptotic cell death [ 104 ]. However, accumulating evidence now indicates that multiple subcellular compartments—including the ER, mitochondria, lysosomes, and the Golgi apparatus—actively participate in the ferroptosis process [ 121 ], with the ER emerging as a central regulatory hub [ 3 , 15 ]. Specific imaging strategies have led to direct in vivo visualization confirming a central role of the ER during ferroptosis [ 122 ]. Considering this crucial role of the ER in the orchestration of ferroptotic signalling, approaches aiming specifically at ER-associated processes hold potential therapeutic value. Specifically, nanoparticle-based systems targeting delivery to the ER exhibit great potential for selective induction of ferroptotic cell death in cancer cells [ 123 ]. Cellular redox homeostasis is mainly impacted by cystine deficiency, which inhibits in the inhibition of System xc − activity, leading to GSH depletion and rendering cells vulnerable to impairment of mitochondrial antioxidant defences. This inhibits DHODH activity mitochondrial DHODH activity, thereby suppressing the conversion ofCoQ 10 conversion to CoQ 10 H 2 and further promoting lipid peroxidation signalling, ultimately triggering ferroptosis [ 111 ]. Oxidative lipidomics analysis further confirmed that the endoplasmic reticulum-mitochondrial contact sites (EMCS) are enriched in PUFAs and represent a primary target for lipid peroxidation. Super-resolution live-cell imaging revealed that phospholipid peroxidation rapidly expands EMCS, thereby facilitating the propagation of oxidative signals to neighbouring mitochondria. This subsequently induces excessive ROS production and accelerates mitochondrial fission [ 124 ]. Consistent with these observations, pan-cancer multi-omics analysis indicates that mitochondrial structural integrity and respiratory efficiency are key determinants of ferroptosis susceptibility. Mitochondrial complex assembly factors, including cytochrome c oxidase assembly protein 18 and cytochrome c oxidase assembly factor 1, have been identified as core regulators linking mitochondrial function to ferroptosis vulnerability [ 125 , 126 ]. Concurrently, CRISPR-based genome-wide screening revealed that lysosomal dysfunction also participates in ferroptosis regulation: the absence of the lysosomal protein pro-saponin leads to lipofuscin accumulation, iron overload, and disrupted ROS homeostasis, thereby promoting ferroptosis [ 127 ]. Moreover, lysosome-targeted delivery of the ferroptosis inducer (5α,8α)-8-(1,1-dimethylethyl)-3-methyl-1,2-dioxaspiro(4,5)decane-3-ethanol (FINO2) induces ferroptosis in an ER-dependent manner, indicating that effective execution of ferroptotic signalling requires inter-organelle communication mediated by the ER [ 3 ]. Lastly, lysosomes have been found as beneficial therapeutic targets for modulating ferroptosis; activating intralysosomal iron pools can mediate the pathways to ferroptosis which brought selective killing in primary sarcoma cells as well as pancreatic ductal adenocarcinoma cells showing up with high expression of CD44 [ 128 ]. Interfering with Golgi apparatus function via substances such as AMF-26/M-COPA, bleomycin A, and Golgi inhibitor A is similarly associated with ferroptosis regulation. The underlying mechanism may involve CoQ10 depletion and redox imbalance [ 129 , 130 ]. Collectively, this evidence suggests that ferroptosis is a multi-organelle phenomenon for which the ER functions as a key regulatory centre for coordinating lipid peroxidation and redox signalling. Thus, targeting ER-mediated pathways emerges as a viable, translatationally relevant strategy for the precise regulation and therapeutic modulation of ferroptosis. In summary, the lipid peroxidation chain reaction is a key driver of ferroptosis, which becomes vastly amplified during the execution stage of ferroptosis and determines ferroptotic signalling progression and the irreversible commitment to killing. Multiple organelles, such as the ER, mitochondria, lysosomes, and Golgi apparatus, have become well defined as the major subcellular sites where ferroptotic processes occur and are composed. These, together, coordinate the structural and metabolic collapse that leads to cell death. Thereby, correct regulation of the lipid peroxidation cascade as well as targeted regulation of the aforementioned organelles are thought to be key means to control cellular ferroptosis. Terminal stage of ferroptosis Plasma membrane rupture Plasma membrane rupture is a hallmark endpoint in several types of RCD, including ferroptosis. Recent papers have determined that membrane disruption in ferroptosis is driven by nanopore structures of only a few nanometers in radius inside the lipid bilayer. As a compensatory mechanism, such cell membrane injury induces an influx of Ca 2+ , which then activates the endosomal sorting complex required for transport (ESCRT)-III machinery. The ESCRT-III complex repairs damaged plasma membranes to counteract the cell death progression of ferroptosis [ 6 , 7 ]. Notably, ESCRT-III is an evolutionarily conserved protein complex that mediates membrane fission and restitution on the occurrence of stress. In addition to its role in ferroptosis, ESCRT-III has a similar activity to preserve the plasma membrane during the execution of other types of RCD, such as necroptosis and pyroptosis. Given its important role in membrane repair and cell survival, ESCRT-III is a promising therapeutic target for regulating ferroptotic sensitivity and, possibly, circumventing drug resistance in cancer therapy [ 131 ]. Propagation among adjacent cells It has been shown that ferroptosis propagates in a cell death wave-like fashion resulting in sequential death of adjacent cells. This cell death propagation is apparently intrinsic to both LPO and iron availability and is observed in morphology as a tendency toward a strong cell swelling phenotype [ 8 ]. Mechanistically, cells with an intact plasma membrane are able to exocytose these oxidised lipid species via vesicles that serve as diffusible mediators for ferroptosis induction in neighbouring cells. Consequently, plasma membrane lipid peroxidation is identified as a defining late event driving ferroptotic signalling amplifying its intercellular propagation [ 3 ]. Subsequent investigations demonstrated that physical neighbourhood plays a role in governing this propagation phenomenon. For example, interference in the α-catenin–dependent cell–cell junctions or chelating of extracellular iron were shown to abrogate ferroptosis propagation further emphasising that this mechanism is highly sensitive to physical contacts and local iron homeostasis. Conversely, promoting intercellular connections either in bridging cells via lipid bilayers or promoting an increased contact surface area between adjacent cells would, in fact, enhance ferroptotic intercellular transmission across the cell population [ 132 ]. Collectively, these findings mark ferroptosis as not being a cell-autonomous phenomenon but rather a coordinated multicellular process whereby both lipid peroxidation and intercellular communication are jointly required to drive the spatial propagation of cell death. Furthermore, FSP1 which participates in iron metabolism, could show detrimental effects of ferroptosis propagation against cells by removing CoQ 10 located on plasma membrane exerting cytoprotective activity [ 20 , 21 ]. Plasma membrane rupture is the hallmark morphological feature of the late stage of ferroptosis and as such both resembles and violates the morphological features of ferroptosis observed in other forms of cancer cell death. However, ferroptosis is distinctly unique from other death modalities in favour of its potential wave-like propagation of ferroptosis in neighbouring cells. This propagation of the ferroptotic signals, which is unique to ferroptosis highlights the cooperativity of lipid peroxidation dynamics. This insight will further provide a theoretical framework for therapeutic targeting of the propagation of ferroptosis to selectively kill tumour cells within a local region. Ferroptosis in different stages of tumour development The process of tumour development can be roughly divided into four functional stages, including the early stage, the progressive stage, the metastatic stage, and the recurrent stage. Tumour cells during the progressive and recurrent stages tend to be endowed with robust ferroptosis resistance, while cells at the early and metastatic stages display significantly heightened ferroptosis sensitivity. The stage-dependent variations in ferroptotic susceptibility offer a conceptual and theoretical framework for ideation of strategically timed ferroptosis-based therapy features targeted to specific phases of tumour development. The complete picture of ferroptotic landscape during early, progressive, metastatic, and recurrent phases of tumour progression is depicted in detail in Fig. 6 . Fig. 6. Open in a new tab Ferroptosis in different stages of tumour development. This figure outlines the principal regulatory networks governing ferroptosis throughout the continuum of tumour development, encompassing the early, progressive, metastatic, and recurrent phases. In the early stage of tumour development ( A ), tumour suppressors such as p53 and BAP1 promote ferroptosis by inhibiting SLC7A11 or activating ACSL4, while the KEAP1-Nrf2 pathway and the ROS-OGT-FOXK2-SLC7A11 pathway exert anti-ferroptotic effects. Overall, ferroptosis demonstrates a tumour-suppressive effect, although some tumour cells adapt through metabolic reprogramming. During the progressive stage ( B ), tumour cells depend on antioxidant pathways such as System xc − -GSH-GPX4, enhancing their resistance to ferroptosis synergistically through the hypoxia-HIF-1α axis in the TME and the TAMs-TGF-β1-HLF-GGT1 axis. In the metastatic stage ( C ), tumour EMT enhances the ferroptosis sensitivity of tumour cells via the ZEB1-PPARγ-ACSL4 axis and the CD44-HA iron endocytosis pathway. In the recurrent stage (Section D), although CSCs possess ferroptotic potential due to high LIP, they can upregulate SLC7A11 through SOX2-DKK1 to develop ferroptosis resistance. BAP1: BRCA1-associated protein 1; SLC7A11: solute carrier family 7 member 11; ACSL4: long-chain acyl-CoA synthetase 4; Nrf2: nuclear factor E2-related factor 2; KEAP1: kelch like ECH associated protein 1; MLL4: Lysine methyltransferase 2B; ROS: reactive oxygen species; OGT: O-GlcNAc transferase; FOXK2: forkhead box A2; DNA: deoxyribonucleic acid; ALOX12: arachidonate 12-lipoxygenase 12 S type; ALOX12B: arachidonate 12- lipoxygenase, 12 R type; FABP3/7: fatty acid binding proteins 3 and 7; LDH: lactate dehydrogenase; GSH: glutathione; GGT1: gamma-glutamyltransferase1; HLF: hepatic leukemia factor; TGF-β1: transforming growth factor-β1; TAMs: tumour associated macrophages; PPARγ: peroxisome proliferators-activated receptors; ZEB1: zinc finger E-box binding homeobox 1; EMT: epithelial-mesenchymal transition; LIP: labile iron pool; FPN: ferroportin; TfR1: transferrin receptor 1; CSCs: cancer stem cells; SOX2: sex-determining region Y-related high mobility group-box 2; DKK1: dickkopf-related protein 1; Wnt/β-catenin: Wingless/Integrated/β-catenin signaling pathway Early stage of tumour development Tumour suppressors p53, BAP1, KEAP1, and lysine methyltransferase 2B (MLL4) have been demonstrated to facilitate ferroptosis within tumour cells in the initial stages of tumorigenesis [ 133 ]. Both p53 and BAP1 negatively regulate SLC7A11 to reduce cystine uptake and render cells hypersensitive to ferroptosis induced by acidic lipids. Interestingly, p53 functions not in a bimodal mode yet exhibits dual roles in regulating ferroptosis under specific conditions highlighting the context-dependent regulation of p53 in guiding redox homeostasis. For instance, classical studies reveal that p53 suppresses SLC7A11 expression, accelerating ferroptosis in tumour cells [ 134 ]. Conversely, under cystine-deprived conditions, p53 enhances p21 protein expression by upregulating the transcription factor CDKN1A. This slows intracellular GSH depletion and reduces reactive oxygen species accumulation, thereby aiding cancer cells in evading ferroptosis [ 135 ]. In contrast to the bidirectional function of p53, downregulation of KEAP1 activates NFE2L2/Nrf2 signalling pathway to boost cellular antioxidant cytoprotective arm hence shielding the cells against ferroptosis [ 35 , 36 ]. Hence, inhibition of NFE2L2/Nrf2 (which is hyperactivated due to KEAP1 dysfunction), has become a bright prospect to reinstating ferroptotic-related metabolism and inhibit tumour growth [ 133 ]. MLL4 is an atypical tumour suppressor acting as co-contributory on addition of regulation. Dysregulation of MLL4 induces downregulation of ferroptosis-enhancing genes (ALOX12, ALOX12B) and upregulation of ferroptosis-suppressing genes (SLC7A11), with this transcriptional reprogramming will accelerates tumour development through reducing ferroptosis susceptibility [ 136 ]. Additionally, NFE2L2/Nrf2 signalling pathway dysregulation was demonstrated regarding time course of tumour progression where a low activity is responsible for fuelling early tumour development and sustained or overactivation leads to therapeutic resistance [ 137 , 138 ]. Preclinical studies in liver cancer also proved this paradoxical behaviour where precise regulation of Nrf2 activity, along with that of p53 and BAP1 is required to strike the fine balance between tumour suppression and ferroptosis resistance [ 35 ]. Traditionally, ROS have been considered the principal drivers of ferroptosis. However, new data in HCC that reported a more context-dependent function for ROS in the regulation of ferroptotic sensitivity emerged. Particularly, the oxidative modification of O-GlcNAc transferase (OGT) at residue C845 of its catalytic domain had shown to activate the enzymatic activity of OGT. As the key enzyme mediating the protein O-GlcNAcylation process, OGT can affect the transcriptional activation of the forkhead box factor A2 (FOXK2) via this type of PTMs. O-GlcNAcylation of FOXK2 increases the affinity for importin α and thereby enhances its nuclear translocation. Once localized in the nucleus, FOXK2 directly binds to the SLC7A11 gene promoter, leading to its transcriptional activation. Increased SLC7A11 expression facilitates the uptake of cystine and increases the antioxidant capacity of the cell, making ferroptosis to be suppressed and thereby causing tumourigenesis in HCC [ 139 ]. Taken together, the presented evidence suggests that ROS can be an inducer/suppressor of ferroptosis, depending on the metastasis and metabolic setting of the TME. Ferroptosis is an inherent tumour suppressor program at the early stage of tumour formation by clearing abnormally dividing or metabolically burdened cells to limit malignant initiation. Subsets of tumour cells can undergo early adaptive responses by undergoing metabolic reprogramming that enable them to escape ferroptotic pressure. This metabolic plasticity not only provides life under oxidative stress but also sets up subsequent mechanisms of malignant transformation and facilitates disease progression. Progressive stage of tumour development In progressive-stage tumours, antioxidant pathways such as System xc − -GSH-GPX4 [ 13 , 138 ], FSP1-CoQ 10 [ 21 , 44 ], DHODH-CoQ 10 [ 111 ], and GCH1-BH4 [ 48 ] are significantly activated, endowing tumour cells with marked resistance to ferroptosis [ 13 ]. The TME plays an important role in governing ferroptosis in tumours in the progressive stage. The hypoxic microenvironment in TME can lead to HIF-1α-activation and drive tumour cells’ resistance to ferroptosis via multiple mechanisms: up-regulating FABP3/7 to enhance formation of LDs, upregulating LDH expression to promote lactate uptake, and enriching transcriptional activity towards promoting intracellular cystine uptake [ 12 , 13 ]. Moreover, tumour-associated macrophages (TAMs) engage in intricate interactions with mitochondria and the TME. TAMs can effectively promote ferroptosis in tumour cells: M1-type TAMs release pro-inflammatory factors (such as ROS species and NO) to enhance lipid peroxidation and thereby facilitate ferroptosis in tumour cells; conversely, M2-type TAMs can upregulate antioxidant pathways to inhibit ferroptosis in tumour cells [ 140 ]. This discovery indicates that TAMs serve not only as immunoregulatory cells within the TME, but also as pivotal regulators of ferroptosis in tumour cells. Their polarisation state and metabolic characteristics directly influence the occurrence of ferroptosis and the anti-tumour immune response. A deeper understanding of this mechanism could provide a theoretical basis for combined therapeutic strategies targeting both immune cells and ferroptosis. Mechanism research reveals, in the progressive stage of tumours, TAMs produce transforming growth factor (TGF)-β1; after TGF-β1 binds to TGF-β receptors on tumour cell’s surfaces, TGF-β1 activates the transcription factor hepatic leukemia factor (HLF). Activated HLF also leads to upregulated expression of gamma-glutamyl transferase 1, which is responsible for decomposing extracellular GSH to produce Cys, providing raw materials for intracellular GSH synthesis in tumour cells and finally benefitting them to improve antioxidant defence strength. This mechanism has been proved in TNBC, in which this significantly promotes ferroptosis resistance in TNBC cells, which is recognized to drive their proliferation, metastatic growth, and resistance to cisplatin [ 141 ]. In advanced tumours, tumour cells become resistant to ferroptosis by upregulating the activity of ferroptosis-suppressive molecules. Such this adaptive switch promotes the ongoing survival of tumour cells and lays the foundation of downstream metastasis. Metastatic stage of tumour development EMT entails the gradual loss of epithelial cellular features such as apical–basal polarity and intercellular adhesion while acquiring the migratory that characteristics and invasive capabilities peculiar to the mesenchymal phenotype, and has been shown to be a concerted process, chronicling tumour progression and therapeutic resistance [ 142 ]. The transcription factor zinc finger E-box-binding homobox 1 promotes epithelial morphological switching of EMT by activating peroxisome proliferator-activated receptor γ, thereby stimulating PUFA biosynthesis and upregulating ACSL4. ACSL4 undergoes a conjugation reaction that reacts PUFAs with CoA to generate PUFA-CoA, which then reduces to esterify the PUFA-CoA producing PUFA-PLs, the main substrates for lipid peroxidation. Thus, EMT‐treated tumour cells exhibit a higher level of oxidizable lipid and increased susceptibility to ferroptosis [ 143 ]. In addition, EMT markedly activates the CD44-mediated hyaluronic acid (HA)-dependent iron uptake. In this pathway, besides iron uptake by CD44, the pathway regulates transcription involving the nuclear iron-mediated positive feedback loop, leading to the concept of iron as a rate-limiting determinant in regulating epigenetic plasticity during the metastatic stage of tumour progression and providing another molecular pathway through which EMT promotes ferroptosis susceptibility in cancer cells [ 144 ]. Melanoma frequently spreads through the lymphatic organs to establish local metastatic niches. Unlike melanoma cells traversing the circulating bloodstream, cells harbouring in lymphatic fluid can utilize oleic acid, one of the MUFAs in the body, to adopt a ferroptosis-adapted mechanism of protection that allows these cells to evade ferroptosis and thus better equip them for establishing metastatic foci [ 145 ]. In contrast, the HIF-1α-heme oxygenase 1 (HMOX1) signalling axis has been reported as a crucial regulator of ferroptosis in bone-resident cells within the environment of melanoma bone metastasis, whereas HMOX1 promotes ferroptotic cell death, whereby stimulating heme degradation and releasing bioavailable iron in cells, further increasing oxidative stress [ 146 ]. Notably, the lymphatic microenvironment differs strongly from that of the bone milieu-high GSH contents and low free iron concentrations collectively constitute a ferroptosis-resistant biochemical environment, upon which, this metabolic signature might have a role, at least partly, in explaining the fact that EMT can benefit in terms of ferroptotic sensitiveness in the case of primary or circulating tumour cells, however paradoxically lymphatic metastases of melanoma are reported to show acquired resistance to ferroptosis [ 145 ]. Together, the above investigations reveal that the different metastatic niches of the same type of tumour can activate distinct ferroptosis regulatory mechanisms, influenced and determined by the metabolic and redox signature that is characteristically present in their environmental compartments. By knowledge of such paradigm-specific ferroptotic profiles we are left with an invaluable anvil for further design of customized, ferroptosis-based biomedical strategies against localised metastasizing tumours. Recurrent stage of tumour development CSCs are a unique subpopulation of tumour cells that possess both self-renewal capacity and tumourigenic potential and play a vital role in tumourigenesis, metastasis, and recurrence [ 147 ]. In innate repair, they are favoured to resist clinical regimens due to their remarkable tolerance to drugs and their intrinsic capacity to effectively repair own DNA [ 148 ]. In terms of metabolism, CSCs are favourably impacted by iron homeostasis. CSCs promotes the acquisiting of iron by upregulating of TfR1 and Tf while simultaneously downregulation of FPN, leading to the accumulation of intracellular LIP to cater to their aggressive requirements [ 149 , 150 ]. This iron-dependent functional trait provides an Achilles’ heel the exploitation of which can selectively wipe out CSCs through induction of ferroptosis [ 133 ]. Nevertheless, the repertoire of CSCs’ adaptive mechanisms to therapy has also been reported. In lung CSCs, sex determining region Y-related high mobility group-box 2 overexpression favourably supported the upregulation of SLC7A11, which facilitates antioxidant protection and offers ferroptosis resistance [ 151 ]. Similarly, Dickkopf-related protein 1, a canonical inhibitor of the Wnt/β-catenin pathway, can also upregulate SLC7A11, shielding CSCs of BC from lipid peroxidation and ferroptotic injury in these populations [ 152 ]. This dichotomy of CSCs-features -both iron-and redox-dependent -makes CSCs extraordinarily sensitive to ferroptotic regulators. Consequently, strategies designed to interfere with iron metabolism to promote lipid peroxidation or inhibit SLC7A11 activity will unequivocally appear as a promising addition to selectively target CSCs populations. Additionally, novel strategies incorporating nanoparticle-based drug delivery systems to increase the intracellular concentration of iron and ROS have been reported as a promising strategy to enable targeted ferroptosis induction in CSCs, introducing a novel strategy for tackling both recurrence and therapeutic resistance [ 153 ]. Finally, tumour cells at various development stages exhibit varying levels of resistance to ferroptosis, indicative of their progressive reprogramming in terms of metabolic and signalling activities. Thus, the select targeting of critical iron-related and ferroptosis-resistant molecules in ferroptosis, and targeting pathways in ferroptosis-inactive tumour stages, based on temporal progression of tumour development, offers promising opportunities to achieve more selective and efficient treatments. Spatial specificity of ferroptosis The TME is a highly dynamic and heterogeneous ecosystem comprised of tumour cells and various non-tumour cell components, including immune cells (e.g., T cells, macrophages, neutrophils), fibroblasts (e.g., cancer-associated fibroblasts, CAFs), vascular cells (e.g., endothelial cells, pericytes) and extracellular matrix (ECM). Together with different cytokines, growth factors, and metabolites, these components collectively regulate tumour initiation, progression, and therapeutic responses [ 154 , 155 ]. Structurally and functionally, the TME can be broadly divided into three major regions: the core hypoxic region, the immune-infiltrated region, and fibrotic region [ 154 ], which correspond closely to the well-characterized desert, inflamed, and excluded tumour immune phenotypes, respectively [ 156 ]. Each compartment is heterogeneously characterized by strikingly differential biological properties - core hypoxic with upregulated HIF signalling and low oxygen tension, immune-infiltrated zone with diverse immune cell subsets with dynamically regulated of tumour immunity, and fibrotic zone to a densely and highly-reconstructed ECM scaffold. Such spatial heterogeneities imbue ferroptosis regulation with remarkable spatial specificity as changing cell composition, oxygen availability, metabolic gradients, and local signalling patterns across the above-compartmentalization converge to develop a complex byline of multifaceted regulation of ferroptosis. A detailed schematic depiction of this underlying architecture of ferroptotic mechanisms in the tumour core, immune-infiltrated regions, and fibrotic compartments is depicted in Fig. 7 , which illustrates an intricate balance between microenvironmental architecture and ferroptosis dynamics. Fig. 7. Open in a new tab Ferroptosis in the spatial heterogeneity of the TME. This figure illustrates the evolving crosstalk between ferroptosis and the spatial heterogeneity of the TME, encompassing the hypoxic core, the immune-infiltrated margin, and the fibrotic stroma. In the hypoxic core ( A ), rapid tumour expansion leads to profound oxygen deprivation, which stabilizes HIF-α through the canonical HIF-PHD oxygen-sensing pathway. Accumulated HIF-α can influence ferroptosis in opposite directions, acting as either a suppressor or facilitator depending on the cellular context and metabolic state. Beyond the HIF axis, hypoxia can attenuate ferroptotic susceptibility through the KDM6A-ACSL4/ETNK1 pathway, revealing an additional layer of regulation that operates independently of HIF signaling. Together, these mechanisms highlight the nuanced role of oxygen tension in shaping ferroptotic dynamics within the tumour core. In the immune-infiltrated region ( B ), innate immune cells (macrophages, DCs, neutrophils, NK cells) and adaptive immune cells (T cells, B cells) participate in ferroptosis regulation and anti-tumour immune responses in either a promoting or inhibiting manner, via mechanisms including changes in polarization status, cytokine secretion, and signal pathway activation. In the fibrotic region ( C ), CAFs form a fibrotic positive feedback loop by secreting ECM components; they primarily inhibit tumour ferroptosis through exosome-mediated molecular transfer or metabolite secretion, while in rare instances, they promote ferroptosis via lncRNA-mediated regulation. TME: tumour microenvironment; lncRNA: long non-coding RNA; PHDs: prolyl hydroxylases; HIF-α: hypoxia-inducible factor α; TfR1: transferrin receptor 1; SLC1A1: solute carrier family 1 member 1; FABP3/7: fatty acid binding proteins 3 and 7; LDH: lactate dehydrogenase; ACSL4: long-chain acyl-CoA synthetase 4; ETNK1: ethanolamine kinase 1; KDM6A: lysine demethylase 6 A; ROS: reactive oxygen species; DCs: dendritic cells; MPO: myeloperoxidase; SLC3A2: solute carrier family 3 member 2; SLC7A11: solute carrier family 7 member 11; IFN-γ: Interferon-gamma; DAMPs: damage-associated molecular patterns; CAFs: cancer-associated fibroblasts; LOXL2: lysyl oxidase like 2; ECM: extracellular matrix; TGF-β: transforming growth factor-beta; Cys: cysteine; GSH: glutathione; ALOX15: arachidonate 15- lipoxygenase; CHAC1: CHAC glutathione-specific gamma-glutamylcyclotransferase 1; FAK: focal adhesion kinase; YAP: Yes-associated protein; TAZ: transcriptional coactivator with PDZ-binding motif Core hypoxic region of the TME and ferroptosis Extensive research has established that hypoxia represents a distinct hallmark of most solid tumours. During uncontrolled tumour cell growth, their rapid proliferation increases metabolic and oxygen demands faster than the delivery system of the venous matrix. This results in the establishment of a hypoxic TME. Here, transcriptional mediators such as HIFs regulate expression of genes promoting anaerobic metabolism and the accumulation of metabolites, reinforcing and perpetuating hypoxic conditions [ 157 ]. Among HIFs, HIF-1α exerts dual regulatory effects on ferroptosis, it on the one hand can upregulate SLC1A1, FABP3/7, and LDH expression to increase cellular antioxidant capacity, thereby conferring resistance to ferroptosis [ 12 , 13 ]. Conversely, HIF-1α promotes ferroptosis by inducing TfR1 expression, which facilitates iron uptake and lipid peroxidation [ 60 ]. HIF-2α, in contrast, largely acts as a pro-ferroptotic regulator, by transactivating genes in lipid and iron metabolism, enhancing cellular susceptibility to ferroptosis, and further increasing ROS levels by irreversible Cys oxidation and propagating ferroptotic death tumour cells [ 158 ]. In the hypoxic TME, HIF-1α-dependent signalling contributes significantly to the development of drug resistance within tumours, while HIF-2α-promoting ferroptosis may represent an exploitable therapeutic vulnerability in overcoming the resistance and restoring ferroptotic susceptibility. This regulatory axis is further refined by the interplay between HIFs and PHDs. The PHDs, a family of α-ketoglutarate- and Fe 2+ -dependent dioxygenases, hydroxylate HIF-α subunits in the normoxic environment, targeting them for degradation through the proteasome pathway. In contrast, under hypoxia, HIF-α is stabilised, resulting in a subset of HIF-α subunits translocates to the nucleus to engage in ferroptosis-related signalling pathways [ 159 ]. Hence, the HIF-PHD oxygen-sensing axis serves as a central molecular connection between tumour hypoxia and ferroptosis regulation, harbouring potential therapeutic targets. Furthermore, in light of specific biochemical properties of the hypoxic zones of the TME, recent developments in pH-sensing functionalized multi-component nanocomposites, which stimulate ROS induction to synergize with the targeted apoptosis induction, have demonstrated high relevance to optimize ferroptosis-based cancer therapies [ 160 ]. Sulphidization-induced ferroptosis requires both ferric iron and the hypoxic response. Beyond traditional HIF-dependent signalling cascades, hypoxia can drive ferroptosis through a variety of epigenetic pathways. Lysine demethylase 6 A (KDM6A), a canonical tumour suppressor gene, has recently been identified as an oxygen-sensing epigenetic regulator. Hypoxia causes hypoactivation of KDM6A activity, as well as that of all oxygen-requiring histone demethylases. Subsequently, KDM6A-mediated transcriptional repression of major ferroptosis-related genes, such as ACSL4 and ethanolamine kinase 1 (ETNK1), occurs. The resultant changes in PL composition and distribution exert inhibitory effects on lipid peroxidation, which further suppresses ferroptosis in tumour cells. Interestingly, this mechanism operates independently of the HIF-PHD oxygen-sensing circuit, unequivocally revealing an additional layer of hypoxia-driven ferroptosis regulation via an epigenetic mechanism [ 161 ]. Altogether, the core hypoxic zone within the TME is characterized by the suppression of ferroptosis, which plays a vital role in the acquisition of drug resistance in tumour cells. The mechanisms underlying this hypoxia-inhibited ferroptosis pathway involve an intricate interplay of signalling cascades and molecular targets, spanning transcriptional and epigenetic regulation. Therefore, therapeutic approaches targeting such hypoxia-mediated inhibitory mechanisms represent a potential strategy for reconstituting ferroptotic susceptibility and reversing resistance to anticancer drugs. Immune-Infiltrated Region of the TME and Ferroptosis It is composed of both innate and adaptive immune cells operating together to form the TME. The primary cells contributing to the innate immune system are macrophages, dendritic cells (DCs), neutrophils and natural killer (NK) cells. In contrast, T cells and B cells are the key cell types constituting the adaptive immune system [ 162 ]. All of these subsets interact with each other in the context of ferroptosis, which is characterized by a tight and context-specific balance. Highly active ferroptosis can decisively determine the fate of tumour progression and immune regulation in the TME [ 162 ]. As summarized in Table 2 , this section provides an overview of the current knowledge regarding regulatory networks linking ferroptosis and immune cells, as well as the implications of regulating ferroptosis in immune cells for tumour immunotherapies. Table 2. The bidirectional regulatory role of ferroptosis in tumour immunotherapy Immune cell types Response to ferroptosis Impact on tumours Key signaling pathways Intervention strategies Preclinical models Ref. CD8 + T cell Prone to ferroptosis (CD36↑). Decreased anti-tumour capacity CD36-lipid peroxidation CD36 antibody + anti-PD-1 Mouse melanoma model [ 190 , 249 ] DCs Suppression of antigen presentation during the early stages of ferroptosis. Enhanced immune tolerance PD-L1-SLC7A11 STING agonist + ferroptosis inducer Head and neck squamous cell carcinoma model [ 171 – [ 173 , 250 ] Neutrophils Release MPO to induce tumour necrosis. Promotes tumour necrosis while suppressing T cells. MPO-halogenation cycle Ferroptosis inhibitor + immune checkpoint blocker GBM [ 162 , 174 , 175 , 251 ] Macrophages (M2) SENP3 de-SUMOylation promotes ferroptosis via FSP1. Reduce immunosuppression and enhance antitumour activity. SENP3-FSP1 SENP3 inhibitor Mouse model of HCC [ 169 ] Regulatory T cells - Presumably affects iron death through metabolic interference. T cell immune receptor with Ig and ITIM domains (TIGIT)-IL-10 TIGIT inhibitor Colon cancer [ 252 – 254 ] B cell Upregulating GPX4 expression suppresses ferroptosis. Lymphoma drug resistance GPX4-GSH GPX4 inhibitor Burkitt lymphoma [ 193 , 255 , 256 ] NK cell L-KYN induces ferroptosis Immunosuppression IDO-KYN Constructing NK cells overexpressing GPX4. GC [ 185 ] MDSCs Spontaneous ferroptosis releases oxidized lipids. Suppression of T-cell function Lipid peroxidation products Ferroptosis inhibitor BC, lung cancer, melanoma [ 179 – 181 ] TAMs Iron overload promotes M1 polarization of macrophages. Promoting ferroptosis in tumour cells. Fenton reaction Iron delivery nanosystem HCC [ 257 – 259 ] Tumour infiltrating lymphocytes (TILs) Cholesterol induces high expression of CD36. Functional exhaustion CD36-lipid peroxidation CD36 blocking antibody BC [ 190 , 260 , 261 ] Open in a new tab Innate immune cells and ferroptosis Macrophages are professional phagocytes with an essential function in clearing ferroptotic tumour cells within the TME [ 163 ]. Regulatory-wise, macrophages play a dynamic role in maintaining cellular iron homeostasis through phagocytosis of senescent red cells, internalization of Tf-bound iron, and absorption of non–Tf-bound iron [ 164 , 165 ]. Functional-wise, macrophages exhibit tremendous plasticity, being polarized into distinct phenotypes broadly designated as M1 and M2, and nonredundantly exerting differential tumour immune response and modulation of ferroptosis. Polarization toward the M1 phenotype can be mediated in response to intracellular iron overload, while iron deficiency shifts macrophage polarization to the M2 phenotype [ 166 ]. More specifically, M1-polarized macrophages can produce significant amounts of ROS, which engages in the Fenton reaction and favours ferroptosis of tumour cells [ 167 ]. In contrast, M2-polarized macrophages indirectly inhibit ferroptosis in tumour cells by interfering with the ferroptosis-promoting functions of CD8 + T cells and suppressing CD8 + T cell activation, ultimately facilitating tumour progression [ 168 ]. Therefore, intracellular iron deficiency not only directly impedes ferroptosis in tumour cells but also further inhibits CD8 + T cell-mediated ferroptosis by inducing macrophage polarization toward the M2 phenotype. Furthermore, a recent study has, for the first time, identified that the redox-sensitive protease SUMO-specific peptidase 3 (SENP3) can enhance the sensitivity of M2-polarized macrophages to RSL3-induced ferroptosis by deSUMOylating the K162 site of the ferroptosis inhibitor FSP1, thereby reducing the proportion of M2-polarized macrophages in vivo [ 169 ]. This study reveals a novel mechanism of SENP3/SUMOylation in regulating macrophage ferroptosis and inflammatory responses, enriches the physiological regulatory network between ferroptosis and macrophages, and provides a new direction for optimizing tumour therapy by promoting ferroptosis in M2-polarized macrophages. DCs are classic antigen-presenting cells (APCs) that play a crucial role in capturing tumour antigens, presenting these antigens, and activating T cells to initiate adaptive immune responses [ 162 ]. DCs play a pivotal role in shaping ferroptosis susceptibility [ 170 ]. Theoretically, tumour cells undergoing ferroptosis may release novel tumour-associated antigens, thereby enhancing the antigen-presenting capacity of DCs. However, experiments involving the co- culture of ferroptotic tumour cells with DCs have demonstrated that tumour cells in the early stages of lipid peroxidation can inhibit the expression of MHC class II molecules in DCs by accumulating LDs. In parallel, tumour cells actively reshape the immune landscape by upregulating immunosuppressive cytokines such as interleukin (IL)-10, while simultaneously downregulating immunostimulatory cytokines including IL-12 and IL-18 [ 171 ]. Collectively, these alterations suppress DC maturation, impair phagocytic capacity, and diminish cross-presentation efficiency, thereby attenuating antitumour immune responses. Moreover, lipid peroxidation has been shown to disrupt the cytoskeletal architecture of DCs, further compromising their migration and antigen-presenting functions [ 171 ]. Emerging evidence also highlights a crucial intersection between immune checkpoint regulation and ferroptosis in DCs. Specifically, programmed death ligand 1 (PD-L1) can bind to and stabilize SLC7A11 mRNA, preventing its degradation. Conversely, loss of PD-L1 expression leads to a reduction in SLC7A11, elevated levels of lipid peroxidation, and subsequent ferroptotic death of DCs, ultimately impairing antitumour immunity [ 172 ]. This intricate molecular interplay establishes a mechanistic link among immune checkpoint inhibitors, ferroptosis, and immune modulation, providing a richer conceptual framework for understanding tumour immunotherapy. Furthermore, the crosstalk between DC function and ferroptosis opens new therapeutic avenues. In head and neck squamous cell carcinoma, activation of the STING–mediated type I interferon (IFN-I) pathway has been shown to enhance DC recruitment and maturation, while IFN-I simultaneously promotes ferroptosis in tumour cells through GPX4 inhibition. The combinatorial application of these strategies synergistically increases DC infiltration, augments ferroptotic efficiency, and substantially improves tumour suppression [ 173 ]. Myeloperoxidase (MPO)-containing neutrophil cytoplasts can generate large amounts of ROS after microbial challenge or inflammatory stimulation. High ROS concentrations activate MPO, which then generates additional reactive intermediates, creating a positive feedback loop that fosters the development of oxidative stress and thereby promotes ferroptosis [ 162 , 174 ]. Specifically, MPO first binds to H₂O₂ to form MPO-Complex I, which exhibits strong oxidative activity. This complex oxidizes halide ions, such as Cl − , to produce hypohalous acids (e.g., HOCl), a process known as the halogenation cycle. HOCl subsequently reacts with H 2 O 2 or O 2 · − to generate singlet oxygen ( 1 O 2 ), ·OH, and chloramines. These reactive intermediates can attack PUFAs on adjacent cell membranes, initiating lipid peroxidation reactions [ 175 ]. At the same time, MPO also catalyses small-molecule substrates, including NO and nitrite, producing MPO–Complex Ⅱ and diffusible, free radicals. This is termed the peroxidase cycle, which can damage the membranes of mitochondria and lysosomes to promote lipid peroxidation chain reactions [ 176 ]. Additionally, LPO undergoes the Fenton reaction under Fe 2+ catalysis, generating more ·OH that further oxidize PUFAs on membranes. Simultaneously, oxidative stress can activate NAD(P)H oxidase 2, which generates H 2 O 2 , thus reactivating the halogenation and peroxidase cycles of MPO [ 175 ]. Together, these interconnected pathways create a self-sustaining oxidative loop driving MPO-dependent ferroptosis in neutrophils. In GBM, neutrophils have been shown to transfer MPO-containing granules into tumour cells and facilitate the accumulation of iron-dependent LPO in tumours, thereby inducing extensive tumour necrosis as the disease progresses [ 177 ]. Before granule excretion, tumour cells can internalize neutrophils via integrating surface molecules, which is dependent on LC3-associated phagocytosis and the PI3K complex (Vps34-UVRAG-RUBCN). Blockage of the PI3K complex is effective in inhibiting the transfer of MPO-containing granules [ 178 ]. Secondly, in the TME, pathologically activated neutrophils and myeloid-derived suppressor cells (MDSCs) undergoing ferroptosis spontaneously release oxidized lipids, thus impairing T cell activity, facilitating tumour immune evasion, and promoting disease progression [ 179 ]. Suppressing ferroptosis in these myeloid populations alleviates this immunosuppressive environment, and in synergy with immune checkpoint inhibitors enhances antitumour efficacy [ 180 , 181 ]. Not only does this discovery elucidate the relationship between neutrophils and the formation of an immunosuppressive TME, but it also reveals that ferroptosis of neutrophils can be a feasible target for cancer immunotherapy [ 180 , 182 ]. Furthermore, in lung adenocarcinoma, neutrophil extracellular traps (NETs) suppress Erastin-mediated ferroptosis of tumour cells via a post‐transcriptional regulatory mechanism, whereby NETs promote solute carrier family 2 member 3 (SLC2A3) mRNA mediated degradation by YTH N6‐methyladenosine RNA‐binding protein F2 (YTHDF2), resulting in downregulation of ferroptotic signalling. Thus, prevention of ferroptosis enhances the proliferative and metastatic capacity of tumour cells [ 183 ]. These discoveries point to the dualism in neutrophils within the TME: they act as mediators and inducers of tumouricidal ferroptosis when undergoing ferroptotic death themselves, making a balance between excessive neutrophil‐induced ferroptosis in tumour cells and immune suppression after ferroptosis in neutrophils an important goal the for effective utilization of ferroptosis in tumour immunotherapy. NK cells are a distinctive innate cell population characterized by direct tumour cell recognition and lysis. However, their capacity for cytotoxicity and immunoregulatory functions is frequently impacted in the TME [ 184 ]. Compared to other innate immune cell populations, the epidemiology and pathology of NK cells remain poorly defined, and the molecular mechanisms underlying the interplay between NK cells and ferroptosis are scarce. In mice, GC are reported to synthesize L-kynurenine (L-KYN) via indoleamine 2,3-dioxygenase (IDO) mediated by enzymatic conversion that promotes ferroptosis for NK cells. Interestingly, NK-92 cells overexpressing GPX4 levels exhibit pronounced resistance to L-KYN-induced ferroptosis. This finding supports a possible therapeutic strategy to enhance the persistence and cytotoxic efficacy of NK cell-based immunotherapies [ 185 ]. Additionally, recent findings demonstrate the ability of microbes to suppress ferroptosis in NK cells through modified iron metabolism. For instance, Bacteroides parabrevis, which is commonly found to colonize human liver cancer tissues, exhibits lipolytic activity, promoting Acetyl CoA generation This metabolite can contribute to enact acetylation of transcription factor RAR-related orphan receptor C, which in turn upregulates the gene NEDD4-like E3 ubiquitin protein ligase (NEDD4L) and enhanced NEDD4L can enlarge the Ubiquitinoses SLC39A14, SLC39A8 and STEAP3, further reducing the intracellular Iron Levels in NK cells through ferroptotic deprivation [ 186 ]. These observations unveil a multifaceted interplay between NK cell metabolism, microbial modulation, and ferroptotic regulation reifying dual roles of the TME and tumour-associated microbiota in NK cell–mediated antitumour immunity. Furthermore, research indicates that mitochondrial dynamics and metabolic adaptability significantly influence NK cell infiltration and effector function within the TME [ 187 ]. Specifically, hypoxia induces mitochondrial fragmentation and oxidative phosphorylation dysfunction via the HIF-1α, mTOR-Drp1 signalling pathway and excessive ROS production. This mechanism has been demonstrated to inhibit NK cell migratory capacity. Concurrently, metabolic stressors such as amino acid deprivation, glutamine or fatty acid metabolism disorders further diminish NK cell survival and functional activity, thereby limiting their antitumour effects within the TME [ 187 ]. Given mitochondria’s critical role in ferroptosis, the interaction between mitochondria and NK cells within the TME expands the scope of ferroptosis in NK cell immune regulation. This suggests that organelle-level ferroptosis metabolic control aids in maintaining NK cell survival and activity within spatially heterogeneous tumour regions. Adaptive immune cells and ferroptosis T cells are the critical effector cells of the adaptive immune system and, as such, possess antigen specificity to recognize epitopes displayed by APCs [ 162 ]. Within the TME, a reciprocal interaction can be observed between T cell functionality and ferroptosis. On the one hand, tumour ferroptotic cells shed immunogenic antigens and damage-associated molecular patterns (DAMPs), which are delivered and processed by APCs augmenting antigen presentation and thus initiate T cell activation and bolster antitumour immune responses [ 14 ]. Conversely, MDSCs, which undergo ferroptotic cell death would secrete inhibitory mediator leading to dampened T cell functions and tumour immune evasion [ 180 , 181 ]. In addition, the CD8 + T cells can inhibit the expression of SLC3A2 and SLC7A11 genes in tumour cells by secreting gamma-interferon (IFN-γ), which depletes intracellular cystine and gradually promotes lipid peroxidation and ferroptosis in tumour cells [ 188 ]. Lastly, the synergy of leucocyte membrane cystine inhibitors and immune checkpoint blockers has been known to amplify T cell-regulated anti-tumour immune response in mouse models and potently induce tumour cell ferroptosis [ 188 ]. Thus, besides regulation of cystine metabolism, IFN-γ regulation can has been found regulate tumour lipid remodelling. By activating ACSL4, IFN-γ would induce AA incorporation into phospholipid (PLs) bearing C16 and C18 acyl chains, making tumour cells more susceptible to lipid peroxidation and consequent ferroptosis thus targeting this “IFN-γ–ACSL4-fatty acid” axis has emerged as attractive therapeutic approach of cancer anti-tumour ferroptosis-based drug [ 189 ]. However, the ferroptotic landscape in the TME would also impact T cell functions. Excess cholesterol can induce aberrant CD36 expression in CD8 + T cells, thereby promoting fatty acid uptake and lipid peroxidation, which consequently impairs their cytotoxic capacity. Genetic ablation or pharmacological block of CD36, or inhibiting ferroptosis of CD8 + T cells, can restore the antitumour function. Furthermore, these treatments work in synergy with programmed cell death protein 1 (PD-1) blockade and contribute to boosting the overall efficacy of tumour immunotherapy [ 190 ]. The RNA methyltransferase phosphorylated CTD-interacting factor 1 (PCIF1) plays a critical role in regulating T cell ferroptosis sensitivity and immune functionality through N6,2’-O-dimethyladenosine (m6Am) RNA modification. Specifically, PCIF1 suppresses the expression of ferroptosis resistance genes, including FTH1 and SLC3A2, as well as the T cell activation marker CD69, thereby compromising the immune effector function of CD8 + T cells. Genetic knockout of PCIF1 confers enhanced resistance to ferroptosis in CD8 + T cells, resulting in more effective tumour suppression and significantly improved therapeutic outcomes when combined with anti-PD-1 therapy or CAR T-cell immunotherapy. Clinically, low PCIF1 expression in patient-derived T cells correlates with better immunotherapeutic responses, highlighting its potential as a predictive biomarker for immune-based cancer therapies [ 191 ]. Beyond PCIF1-mediated regulation, recent findings from sickle cell disease (SCD) models have revealed that alterations in the three-dimensional chromatin conformation of CD8 + T cells lead to the downregulation of ferroptosis resistance genes, including SLC7A11 and hydrogen sulfide (H 2 S) synthases. This disruption increases T cell vulnerability to ferroptosis, offering mechanistic insights into the higher tumour susceptibility observed in SCD patients. These observations further suggest that modulation of the H 2 S signalling axis may provide a novel avenue for precision immunotherapy tailored to this patient population [ 192 ]. While current research has predominantly centred on CD8 + T cells, the functional interplay between CD4 + T cells, ferroptosis, and tumour immunity remains insufficiently characterized. Elucidating these mechanisms will be essential for achieving a comprehensive understanding of ferroptosis-mediated immune regulation in cancer. B lymphocytes are important effector cell of humoral immunity. Generally, they recognize antigens through surface receptors and subsequently differentiate into plasma cells and memory B lymphocytes. Plasma cells make specific antibodies that neutralize antigens. Memory B cells are activated quickly upon re-exposure of the same pathogen. Like T cells, immunogenic antigens as well as DAMPs released by tumour cells undergoing ferroptosis can activate B cells, and their activation and production of antibodies enhance the humoral immune response [ 162 ]. Moreover, certain types of viruses found in tumours reverse ferroptosis in tumour cells through B cell modulation. For example, Epstein-Barr virus (EBV) can stimulate lipid metabolism to convert B cells into lymphoblastoid cell lines, which generate lipid ROS. Burkitt lymphoma cells infected with EBV rely on GPX4-GSH pathway to eradicate lipid ROS that damage them. Consequently, inducing ferroptosis in tumour cells by inhibiting the GPX4 pathway has become a novel therapeutic strategy for certain EBV-related lymphomas [ 193 ]. When malignant transformation occurs, B cells exhibit ferroptosis resistance. Diffuse large B-cell lymphoma (DLBCL) is a kind of malignancy that arises from B cells. DLBCL bearing the germinal centre B cell-like phenotype activates the FSP1-mediated ferroptosis resistance pathway via BRD4 from the bromodomain and extra-terminal domain proteins (BET). This increase causes drug resistance in tumour cells; according to study, BET inhibitors enhance tumour cell sensitivity to ferroptosis inducers through downregulation of the BRD4-FSP1 pathway [ 194 ]. The interaction mechanism between immune cells and ferroptosis within the TME is exceedingly complex, making the development of tumour immunotherapeutic strategies that leverage ferroptosis mechanisms critically important. Among these strategies, safeguarding immune cells from ferroptotic damage stands out as a pivotal approach to enhancing the efficacy of tumour immunotherapy. This endeavour necessitates a deeper understanding of the underlying regulatory mechanisms governing both the regulation of immune cell ferroptosis and the induction of ferroptosis in tumour cells. Fibrotic region of the TME and ferroptosis CAFs and the fibrotic milieu they orchestrate play a multifaceted—and at times paradoxical—role in modulating ferroptosis within tumour cells. This dualistic function, which can both hinder and facilitate ferroptotic processes depending on the contextual cues of the TME, represents a crucial determinant of therapeutic responsiveness. While fibrosis-driven protection against ferroptosis contributes to treatment resistance, the same pathways may also be harnessed to uncover new vulnerabilities, offering a conceptual framework for the development of innovative ferroptosis-oriented therapeutic strategies. Fibroblasts, immune cells, and the ECM make up the fibrotic tumour niche [ 195 ]. CAFs, as an important component of the TME, secretes large amounts of ECM components like type I, type III, type V, and type XI collagen; fibronectin, tenascin C, and laminin, which promotes the deposition of these components at the tumour margin and within the tumour parenchyma. In addition, CAFs release lysyl oxidase like 2, which helps to harden tissue by converting collagen into a non-soluble material. This increased rigidity activates CAFs via the integrin-FAK-Src-YAP/TAZ signalling pathway. As a result of such activation, the CAFs secrete ECM and pro-fibrotic factors, including TGF-β, connective tissue growth factor and IL-11, to the extent that a positive feedback loop called “fibrosis-CAFs loop” is established [ 196 ]. The fibrotic characteristics of the TME are shaped by the interaction between CAFs and the ECM, and this poses significant challenges for tumour therapy. The fibrotic TME can inhibit ferroptosis in tumour cells through multiple mechanisms, thereby inducing chemoresistance. In GC cells, CAFs package miR-522 into exosomes via the USP7/hnRNPA1 axis, and chemotherapeutic drugs can further promote this process. Once exosomes containing miR-522 are delivered to GC cells, they inhibit the expression of ALOX15, block the accumulation of lipid ROS, and ultimately suppress ferroptosis, thereby reducing the sensitivity of GC cells to chemotherapeutic agents [ 197 ]. Additionally, CAFs in GC can release Fe 2+ into the TME by highly expressing FPN, leading to ferroptosis in NK cells due to iron overload and impairing anti-tumour immunity [ 198 ]. In PC cells, CAFs target and inhibit the expression of ACSL4 in cancer cells via miR-3173-5p contained in exosomes, blocking gemcitabine-induced ferroptosis and enhancing their chemoresistance in PC cells [ 199 ]. Meanwhile, CAFs can activate the transsulfuration pathway through the TGF-β/SMAD3/ATF4 axis, secreting substantial amounts of Cys, and providing precursors for GSH synthesis in PC cells, which inhibits ferroptosis and enhances their radioresistance [ 200 ]. In prostate cancer (PCa), miR-432-5p carried by CAF-derived exosomes can target and inhibit the expression of CHAC Glutathione-Specific Gamma-Glutamylcyclotransferase 1, reducing GSH consumption, mitigating lipid ROS accumulation and mitochondrial damage, and ultimately suppressing ferroptosis in PCa cells, thereby inducing resistance to docetaxel [ 201 ]. However, some studies have proposed an opposing conclusion: lncRNA DACT3-AS1, delivered by CAF-derived exosomes, can trigger ferroptosis in GC cells by sequestering miR-181a-5p and upregulating the expression of sirtuin 1 (SIRT1). This mechanism inhibits the proliferation, migration, and invasion of GC cells, as well as their resistance to oxaliplatin, a finding corroborated by both in vitro and in vivo experiments [ 202 ]. This contradictory result may be attributed to variations in the content of CAF-derived exosomes; however, the regulatory mechanisms underlying these differences require further investigation for clarification and validation. The dual role of CAFs in inducing ferroptosis in tumour cells through ECM regulation presents challenges for achieving spatially targeted tumour therapies. Therefore, elucidating the intrinsic pathways involved in the interaction between CAFs and ferroptosis is crucial for optimizing ferroptosis-based therapeutic strategies for tumours. In summary, the heterogeneity of the TME influences a delicate and complex regulatory relationship between cells in different regions of the TME and ferroptosis. This relationship involves multiple signalling pathways and regulatory molecules. Further elucidating the mechanisms of action of these signalling pathways and molecules not only aids in achieving precise targeting of cells in various TME regions but also holds significant theoretical and clinical implications for overcoming tumour treatment resistance and enhancing the synergy between ferroptosis and tumour immunotherapy. To further integrate the intricate regulatory network of ferroptosis, Fig. 8 systematically summarises the comprehensive landscape of ferroptosis across three dimensions: spatiotemporal dynamics, organelle functional coupling, and TME interactions. Fig. 8. Open in a new tab The triggering, execution and immune metabolic interaction mechanisms of ferroptosis. This diagram systematically illustrates the initiation, execution, and TME interaction processes of ferroptosis. Part A: The initiation phase triggers the death signal through the combined effects of System Xc − inhibition leading to GSH depletion and GPX4 inactivation, coupled with TfR1-mediated iron ion uptake and ACSL4-induced accumulation of lipid substrates. Section B: The execution phase centres on lipid peroxidation chain reactions. FSP1, DHODH, and GCH1 form a multidimensional defence system, whilst lysosomes release iron ions via ferritin autophagy, amplifying mitochondrial ROS-mediated lipid damage. Part C: The interaction phase reveals the link between ferroptosis and the immune microenvironment. CD8 + T cells (via IFN-γ) and M1 macrophages (via the Fenton reaction) synergistically enhance ferroptosis susceptibility, a process profoundly regulated by metabolic factors including hypoxia and HIF-1α.System Xc − : Cystine/glutamate antiporter system; SLC7A11: Solute carrier family 7 member 11; SLC3A2: Solute carrier family 3 member 2; GSH: Glutathione; GPX4: Glutathione peroxidase 4; TfR1: Transferrin receptor 1; Tf: Transferrin; STEAP3: Six-transmembrane epithelial antigen of prostate 3; DMT1: Divalent metal transporter 1; LIP: Labile iron pool; PUFAs: Polyunsaturated fatty acids; ACSL4: Acyl-CoA synthetase long-chain family member 4; LPCAT3: Lysophosphatidylcholine acyltransferase 3; PUFA-PE: PUFA-containing phosphatidylethanolamines; FSP1: Ferroptosis suppressor protein 1; IFN-γ: Interferon-γ; HIF-1α: Hypoxia-inducible factor 1α; DHODH: Dihydroorotate dehydrogenase; GCH1: GTP cyclohydrolase 1 Ferroptosis-based tumour therapeutic strategies The induction of ferroptosis in tumour cells represents a novel therapeutic strategy for cancer, especially for those tumours unresponsive to apoptosis-inducing therapies. Several ferroptosis inducers, such as erastin, RSL3, and SRF, have demonstrated potent anti-tumour efficacy in preclinical studies [ 203 ]. This section aims to introduce well-characterized ferroptosis-inducing drugs for tumour therapy and, based on the spatiotemporal specificity of ferroptosis in tumour cells, supplement the application of emerging nanomaterials in this field. Ferroptosis-based tumour therapeutic drugs and their derivatives SRF SRF is a multi-targeted tyrosine kinase inhibitor that exhibits dual effects: it inhibits tumour proliferation and anti-tumour angiogenesis. Approved by the FDA for the treatment of solid tumours such as advanced RCC and HCC, SRF is also a well- established inducer of ferroptosis with a clearly defined mechanism of action [ 203 ]. SRF exerts its ferroptosis activity via inhibition of the SLC7A11 located on the cell membrane, which blocks the cystine/glutamate antiport. This, in effect, leads to impaired intracellular GSH synthesis and ER stress, further impairment of the GPX4 activity, leading ultimately to ferroptosis in cells [ 4 ]. The emergence of resistance to SRF represents one of the key challenges in its clinical application. This occurs due to complex and heterogeneous resistance mechanisms. Firstly, the activity of SRF can inactivate KEAP1, which leads to activation of the NFE2L2/Nrf2 and increasing the GPX4 expression levels. This weakens the ferroptosis-inducing effect of SRF, resulting in SRF resistance [ 35 , 36 ]. Results from CRISPR screening also demonstrate that COP9 signalosome subunit 5 (COPS5) can stabilize the mitogen-activated protein kinase 2 via its deubiquitinating mechanism, subsequently leading to activation of the heat shock protein β-1, which in turn inhibits ferroptosis. SRF can also upregulate COPS5 expression via the ATF4, and thereby establishes a positive feedback loop, contributing to the drug resistance [ 204 ]. Furthermore, the expression of interferon-stimulated gene 15 (a ubiquitin-like modifier protein) mRNA is stimulated by SRF via the STING pathway, through the interference of interferon regulatory factor 3 mediated, inhibiting ubiquitination and degradation of the deubiquitinating enzyme ubiquitin-specific protease 18(USP18). Subsequently, the elevated intracellular USP18 leads to inhibiting the effect of SRF on ferroptosis via promoting the deISGylation and degradation of NCOA4, resulting in the resistance of HCC [ 205 ]. In order to develop drug resistance–avoiding strategies and overcome drug resistance of the current model of medical treatment, researchers have designed structural optimizers to enhance the ferroptosis-inducing effects of SRF. Among them, compound N-2-c1, an SRF structural optimizer with the sulfonamide group as a linker. Compared with the parent drug, the structure depicts a noticeably stronger affinity to GPX4. They can also markedly increase the levels of intracellular ROS and MDA content, which promotes lipid peroxidation as well as the destruction of membrane and mitochondrial membrane potential (MMP), and induced alternative mechanism to achieve more efficient ferroptosis in tumour cells [ 206 ]. At the present stage, the resistance mechanism of the SRF is the major limiting factor of its clinical application for tumour ferroptosis therapy. Further clarification of the mechanisms of resistance of HCC cells to SRF is likely to ameliorate the longstanding obstacles in the therapy of HCC and provide new avenues for ferroptosis-targeted therapy. Nonetheless, validation of SRF in additional tumour types is necessary in the near future. Sulfasalazine (SAS) SAS, an azo-bridged anti-inflammatory drug, is mainly used to treat chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis [ 203 ]. Like the ferroptosis induction mechanism of SRF in tumour cells, SAS is also a strong inhibitor of System xc − . By inhibiting cystine uptake and decreasing the content of intracellular GSH [ 207 ], it has disrupted the cell’s safeguard against ferroptosis. At least five different cancers have strongly demonstrated the mechanism of ferroptosis and SAS-induced ferroptosis in tumour cells. In CRC, Trifluridine/Tipiracil (FTD/TPI) can downregulate SLC7A11 and GPX4 through the p53-SLC7A11 axis, among them, SAS significantly improved the inhibitory effect of FTD/TPI and other factors, which could effectively inhibit the proliferation and migration of CRC cells [ 208 ]. In esophageal cancer (EC), since tumour cells are surrounded by a severely hypoxic microenvironment, SAS activated the ferroptosis pathway by downregulating SLC7A11 and GPX4 while upregulating ACSL4 expression level, which ultimately inhibited the proliferation of EC cells manner [ 209 ]. Notably, in BC, the estrogen receptor inhibits TfR; thus, BC subtypes with low estrogen receptor expression exhibit heightened sensitivity to SAS-induced ferroptosis therapy [ 210 ]. In gliomas, the hypoxic microenvironment upregulate SLC7A11 expression through the activation of the PI3K/AKT/HIF-1α axis, significantly inhibiting SAS-induced ferroptosis in glioma cells [ 211 ]. Together, these results highlight the need for establishing therapeutic approaches to ferroptosis-promoting drugs based on cell type targeting the heterogeneity of the TME. According to recent papers, in osteosarcoma (OS), while the SAS exerts tumour-killing effects via inhibition of Nrf2/SLC7A11/GPX4 signalling axis, it appears that the cytotoxic effect is highly dose dependent [ 212 ]. Thus, a development of novel SAS-based formulations for the SAS that induce effective tumour cell killing should be the focus to also overcome the dose dependency of the SAS as well as to reduce drug toxicity. Notably, the cobalt (III) polypyridine sulfasalazine complex is the first cobalt (III) polymer capable of inducing ferroptosis. Upon entering cancer cells, this polymer predominantly accumulates in mitochondria, leading to the generation of ·OH and the accumulation of LPO, and ultimately triggering ferroptosis in cancer cells. Studies have demonstrated that this polymer can effectively eliminate various monolayer-cultured cancer cells as well as colon cancer multicellular tumour spheroids [ 213 ]. Erastin and Its Derivatives Erastin is a well-established ferroptosis inducer that triggers ferroptosis in tumour cells through multiple pathways. First, erastin interacts with mitochondrial voltage-dependent anion-selective channels, leading to a decrease in MMP and subsequent mitochondrial dysfunction. This dysfunction increases the production of mitochondrial ROS, further exacerbating lipid peroxidation [ 214 ]. Second, erastin inhibits the activity of System xc − , which blocks cystine uptake and results in the accumulation of intracellular lipid ROS, ultimately triggering ferroptosis [ 2 ]. This mechanism has been validated in various tumour models, including HCC, GC, and lymphoma [ 215 ]. Recent studies have also uncovered a novel mechanism of erastin-induced ferroptosis: in colon cancer cells, erastin significantly inhibits the expression of male-specific lethal 1 (MSL1) while upregulating the expression of potassium channel tetramerization domain-containing 12 (KCTD12). MSL1 promotes erastin-induced ferroptosis in human colon cancer cells (HCT116, SW480) via the KCTD12-SLC7A11 axis [ 216 ]. Given the inherent limitations of erastin [ 217 ], it is essential to develop combination therapies that incorporate other ferroptosis inducers alongside erastin derivatives. For instance, dihydroartemisinin (DHA, an artemisinin derivative) targets iron metabolism pathways can synergistically promote ferroptosis in PC cells in conjunction with erastin by elevating intracellular free iron levels [ 218 ]. Imidazole ketone erastin (IKE), a derivative of erastin, has been shown to inhibit System xc − in DLBCL. In DLBCL xenograft mice, a single IKE administration induces lipid peroxidation and a significant dose-dependent tumour growth suppression via ferroptosis [ 219 ]. For erastin under altogether, there are still some limitations, such as poor water solubility, insufficient targeting ability, a narrow therapeutic window and clinic drug development, which were limiting to clinical translation and application of erastin and its derivatives [ 217 ]. In the future, nanodelivery systems for erastin will address the bottleneck in its clinical translation by targeting these limitations [ 220 ]. Statins Apart from their classical inhibitory effects on System xc − , statins are a rare class of ferroptosis inducers, acting on mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, a central metabolic checkpoint for ferroptosis defence [ 221 ]. Furthermore, experimental evidence has demonstrated that in MDA-MB-231 cells, a mouse model cancer epithelial type cells of TNBC, autophagy-triggered ferroptosis can specifically induced pitavastatin acting through the mevalonate pathway [ 222 ]. Last but not least, in addition to inducing ferroptosis via the mevalonate pathway, inhibiting this pathway can further promote ferroptosis through downstream signaling axes such as the ILF3-SLC7A11 axis. Taking GC cells as an example, simvastatin can promote ferroptosis by inhibiting ILF3 expression as well as SLC7A11/GPX4 levels and this is specifically represented by the increased levels of intracellular Fe 2+ , ROS and MDA and decreased GSH levels [ 223 ]. Despite the vast, and yet compelling preclinical evidence, greater than ever before the translational potential of statin as ferroptosis inducers in oncology has still left much to be explored. Among the main issues, are how to modify the conventional dose used in cardiology from those used in anti-tumour activity, how to control the musculoskeletal side effects that could be caused by the CoQ 10 depletion and that benchmarks like the activity of mevalonate pathway could benefit to using biomarkers to screen patient populations most likely to these reagents to be capable of benefitting from the combined therapeutic approach, the combined use of statins and other ferroptosis sensitizers should be tested by prospective clinical trials to confirm this therapeutic approach. Application of nanotechnology in inducing tumour ferroptosis Due to poor water solubility, low stability, insufficient targeting, and considerable interference from TME, etc., existing ferroptosis inducers and ferroptosis-oriented tumour therapeutic drugs come with severe limitations [ 224 ]. These challenges severely restrict their application in ferroptosis-oriented tumour therapy and hinder clinical translation. Nanotechnology offers a multifunctional platform that can address the core limitations of traditional ferroptosis inducers. By designing intelligent nanocarriers, researchers can enhance drug delivery efficiency and bioavailability while creating multifunctional therapeutic systems that synergistically amplify ferroptosis-inducing effects and remodel the immunosuppressive TME [ 220 ]. Table 3 summarizes various multifunctional synergistic therapeutic systems related to ferroptosis-based nanodrugs. Table 3. Multifunctional synergistic therapeutic system of ferroptosis nanodrugs Nano system name Payload components Response mechanism Synergistic treatment approach Targeted cells /organelles Animal model Ref. CACuPDA PDA, CA, Cu 2+ GSH Ferroptosis, cuproptosis, immunotherapy Lung cancer cells /lysosomes Lung cancer [ 228 ] NSeMON-P@CuT/LipD Pemetrexed (Pem), diselenide-bonded mesoporous organosilicon nanoparticles (SeMON), Cu 2+ GSH Ferroptosis, Cuproptosis, apoptosis BC cells /mitochondria BC [ 262 ] HA-CS@PtNP-GOx CS, ptNPs, GOx Low pH Autoperoxidation, ·OH generation, ferroptosis Cervical cancer cells /lysosomes Cervical cancer [ 160 ] DOX/Fe³⁺/EGCG NPs DOX, Fe³⁺, epigallocatechin gallate (EGCG) Low pH Ferroptosis, chemotherapy Lung cancer cells /lysosomes Lung cancer [ 263 ] mHFn@RSL3/iFSP1 RSL3, iFSP1 Low pH Inhibition of the GPX4 and FSP1 antioxidant defense pathways. CRC cells/ cell membrane CRC [ 264 ] FeOOH@Fe-Ap@Au NSs FeOOH cores, Ap coating, Au nanodots Glucose Metabolic reprogramming, ferroptosis Ovarian cancer cells/mitochondria Ovarian cancer [ 265 ] FeCP@PDA-GOx FeCP core particles, PDA, GOx Glucose/ low pH Hunger therapy, catalytic therapy, mild PTT, immunotherapy Melanoma cells/ cell membrane Melanoma [ 266 ] SRF@Fe (III)-COF SRF, Fe 3+ Low pH, GSH Chemical Kinetics, Immune Activation HCC cells /mitochondria HCC [ 225 ] OD-M Oliveirado, DHA ROS Consumes GSH, increases ROS GC cells /cell membrane GC [ 267 ] siMCT4-PAMAM-PEG-TK-Fc@DEM Ferrocene (Fc), diethylmaleate (DEM), monocarboxylic acid transporter protein 4 inhibiting siRNA (siMCT4) ROS Catalyze lipid peroxidation, disable antioxidant defenses, acidify the intracellular environment. BC cells/ cell membrane BC [ 268 ] CM-DSe-SRF-Fe 2+ SRF, Fe 2+ , diselenide-linked levodopa (DSe) ROS, GSH Inhibiting GPX4, increases ·OH Lung cancer cells/ cytoplasm/ cell membrane Lung cancer [ 269 ] DP-HBN/RA RSL3, diABZI Low pH Ferroptosis, STING pathway activation TNBC cells/ cell nucleus TNBC [ 230 ] CSIR SRF, Cu 2+ , IR780 PTT/PDT, EPR effect Ferroptosis, PDT, PTT OS cells/ mitochondria OS [ 231 ] ssP-tHB@Fe/DOX Doxorubicin, Fe 3+ GSH consumption, mitochondrial targeting Chemotherapy, Ferroptosis, Apoptosis Lung cancer cells/ mitochondria Lung cancer [ 229 ] Open in a new tab Nanosystems loaded with ferroptosis inducers The delivery efficiency of SRF is improved due to the Fe(III)-based covalent organic framework (COF) nanoplatform constructed by loading SRF (SRF@Fe(III)-COF), which induces ferroptosis effect and also effectively eliminates the drug resistance of the tumour. This nanosystem mediates both peroxidase-like and GSH oxidase-like activities in the acidic TME. On one hand, it catalyzes H 2 O 2 to produce large quantities of ·OH, which in turn stimulates lipid peroxidation. On the other hand, it removes high intracellular GSH levels, affecting tumour cell defences and antioxidant levels. In addition, it enhances calreticulin exposure on tumour cell surfaces and induces the release of high-mobility group box 1 protein, which activates DCs and promotes CD8 + T infiltration within the tumour region. When used together with PD-1 inhibitors, this system has a significant synergistic anti-tumour effect, with inhibition of the primary tumour as well as distant tumours [ 225 ]. Self-etching platinum-cobalt nanodendrites (Pt/Co-BNN) loaded with SAS (Pt/Co-BNN@SAS) are employed to induce ferroptosis in bladder cancer (BCa) cells. Pt/Co-BNN utilizes its peroxidase activity to consume H 2 O 2 , generating ·OH while simultaneously depleting intracellular GSH. Meanwhile, SAS inhibits cystine uptake in tumour cells by blocking System xc − , which further accelerates GSH depletion. The rapid reduction of GSH significantly promote the accumulation of LPO and inhibit GPX4 activity, ultimately leading to efficient ferroptosis induction in BCa cells suppressing their migratory capacity [ 226 ]. Hydroxyethyl starch-polycaprolactone nanoparticles co-load doxorubicin (a chemotherapeutic agent) and erastin. Erastin inhibits the efflux of doxorubicin, both intracellular and extracellular, by depleting intracellular GSH, leading to increased drug accumulation. In addition, erastin enhances the generation of ROS induced by doxorubicin. This nanosystem can effectively eliminate cancer cells and CSCs. It has also been shown to severely inhibit the growth, metastasis and recurrence of TNBC cells in suitable TNBC cell models [ 227 ]. IKE is delivered via polyethylene glycol-polylactic-co-glycolic acid nanoparticles. This nanodelivery system has been proven to the reduce toxicity of compared to free IKE [ 219 ] (Table 4 ). Table 4. Treatment strategies for ferroptosis in combination with other forms of RCD Combined death modes Synergistic mechanisms Inducers/ nanosystems Tumour types Efficacy in animal models Clinical translation stage Ref. Ferroptosis + apoptosis Inhibition of PI3K/AKT-induced ferroptosis and apoptosis. CDDO-Me Cervical cancer Effective in vivo Preclinical research [ 270 ] Ferroptosis + pyroptosis Moderate doses induce ferroptosis, while high doses induce pyroptosis. Fe(hino) 3 OS - Preclinical research [ 271 ] Ferroptosis + cuproptosis Consumes GSH, blocks Cu 2+ efflux Fe/Cu-HPC@GOx/PEG BCa Effective in vivo Preclinical research [ 272 ] Ferroptosis + necroptosis mPTP open, RIPK1 phosphorylation Iron overload, ischemia-reperfusion - Neuroprotective effect Basic research phase [ 73 ] Ferroptosis + autophagy ROS induces mitochondrial autophagy and ferroptosis. LF-V4 NPs GBM Effective in vivo Preclinical research [ 273 ] Ferroptosis + immunogenic cell death Inhibition of GPX4 and immune checkpoints. αPD-1@Lv/HPAGel TNBC Effective in vivo Preclinical research [ 274 ] Ferroptosis + cellular senescence First induce cellular senescence, then eliminate it through ferroptosis. Cisplatin, RSL3 High-grade serous ovarian cancer - Preclinical research [ 275 ] Ferroptosis + metabolic reprogramming Disrupting the oxidative balance of tumour cells. G-PA4/E NPs PC Effective in vivo Preclinical research [ 276 ] Ferroptosis + epigenetic regulation DNMT inhibitors + ferroptosis inducers Decitabine + erastin Myelodysplastic syndromes Effective in vivo Preclinical research [ 277 – 279 ] Iron Death + vascular normalization Inhibit VEGF to improve the TME. Bevacizumab CRC Effective in vivo Preclinical research [ 280 , 281 ] Open in a new tab Stimuli-responsive nanosystems Tumour cells undergo ferroptosis with high spatiotemporal specificity, which complicates ferroptosis-based tumour therapy. Nevertheless, stimuli-responsive nanomaterials can effectively overcome the ferroptosis resistance in tumour cells due to the temporal specificity of tumours and spatial specificity of the TME due to their excellent spatiotemporal regulation capabilities. Nanosystems that respond to stimuli can be classified as internal stimuli-responsive and external stimuli-responsive. Systems that respond to internal stimuli can accurately induce ferroptosis in tumour cells by leveraging tumour-associated features. In contrast, external stimuli-responsive nanosystems mainly exert a therapeutic effect by reacting to external stimuli such as ionizing radiation, light, and ultrasound [ 220 ]. Given the spatiotemporal specificity of ferroptosis in tumour cells, responsive nanosystems to internal stimuli are more prominent. Nanosystems responsive to internal stimuli (include pH and GSH) that can induce ferroptosis are also available to accurately induce ferroptosis of tumour cells according to the heterogeneity of the TME [ 220 ]. To obtain the pH specificity, a nanocomposite known as HA-CS@PtNP-Gox (HCPG) has been developed, which contains platinum nanoparticles (PtNPs) stabilized by HA and CS. This system can efficiently load glucose oxidase (GOx) and specifically induce ferroptosis in tumour cells within the hypoxic region of the TME. To summarize, it is interesting to note that HA can bind to the membrane of CD44 receptor selectively. Its presence in the formulation enables the formation of stable CS/HA nanocomposites via electrostatic interactions, while also enhancing biocompatibility and preserving the activity of GOx. PtNPs can act in a cascade reaction with GOx to produce ·OH and oxidize intracellular GSH under acidic conditions. This system can efficiently induce tumour ferroptosis through various engagement pathways [ 160 ]. The HCPG system makes good use of the low-pH feature of the TME and stabilises the activity of GOx using its composite structure. This guarantees that the medication is delivered specifically and safely to the site. Researchers have developed a targeted nanosystem CACuPDA composed of polydopamine PDA as the carrier backbone loaded with cinnamaldehyde (CA) and Cu 2+ to target GSH. This system aims to deplete GSH and inhibit GPX4 activity. The underlying mechanism is that CA can induce the generation of ROS, while Cu 2+ can directly deplete GSH and inhibit GPX4 activity. Together, these components synergistically enhance the ferroptosis effect in cells. Also, Cu 2+ can trigger cuproptosis; in its reduced state, its catalytic activity converts intratumoral H 2 O 2 into ·OH, thereby amplifying oxidative stress. In an in vivo study of lung cancer, the efficacy of anti-PD-L1 therapy was enhanced fivefold in the presence of the nanosystem, versus baseline levels [ 228 ]. The CACuPDA system may slightly activate some pathways that inhibit ferroptosis even though it promotes ferroptosis via multiple pathways. Still, it can integrate mechanisms of cuproptosis and ferroptosis, providing a novel model of synergistic anti-tumour therapy through multiple RCD forms and facilitating their clinical translation. Relying on the robust designability of nanosystems, those that induce ferroptosis through multiple pathways demonstrate significant application prospects. For instance, an intelligent polymer nanoparticle (ssP-tHB@Fe/DOX) can catalyse multi-pathway GSH depletion, inhibit GPX4, and disrupt mitochondrial function via iron ion cycling mediated by 3,4,5-trihydroxybenzaldehyde (tHB), thereby synergistically enhancing the ferroptotic effect. At the same time, the given doxorubicin increases the extent of the Fenton reaction by inhibiting NAD(P)H and also stimulates apoptosis [ 229 ]. The DSPE-PEoz-modified hollow Bi₂Se₃-RSL3/diABZi (DP-HBN/RA) nanodrug, which exhibits pH responsiveness, exerts significant therapeutic effects on TNBC via radiosensitization, enhanced ferroptosis, and immune activation. This system concentrates the energy of X-ray radiation in cancer cells, causes cancer cell death, and generates large amounts of ROS. Also, in the low-pH TME, DP-HBN/RA is involved in RSL3-induced GPX4 inactivation; these two pathways (radiosensitization and GPX4 inactivation) synergistically drive ferroptosis in TNBC cells. In addition, DP-HBN/RA aggravates unwinding damage and DNA release of sufficient size, which might activate the cGAS-STING pathway and thereby leading to a systemic immune response [ 230 ]. CSIR is an ultrafine nanodrug that avoids the use of any carrier, enabling it to penetrate tumor tissues through the EPR effect. The Cu 2+ in it interacts with the reduced intracellular environment to deplete GSH; SRF released by CSIR inhibits GSH biosynthesis through blocking System xc − . When CSIR is exposed to near-infrared light, it creates ROS to further diminish GSH, thereby achieving the synergistic use of OS ferroptosis, PDT, and PTT application [ 231 ]. Nanotechnology can build tailored ferroptosis-inducing systems for the treatment of tumours, including lung cancer [ 229 ], TNBC [ 230 ], and OS [ 231 ]. This fully shows the broad prospects of nanotechnology in tumour therapy and has attracted many scholars’ attention. However, the application of nanosystems in ferroptosis therapy for tumours is not without problems. Degradation products of nanomaterials may, for example, cause oxidative damage to normal tissues; nanocarriers may interact with protein coronas in the bloodstream, which can increase particle size or result in clearance by the reticuloendothelial system. Tumour cell heterogeneity can also create a lack of targeting sites on certain tumour cells, enabling these cells to undergo immune escape [ 232 ]. From a clinical translation perspective, despite the design of various targeted nanosystems, the information on their large-scale production, quality control, and in vivo pharmacokinetics is far from sufficient which greatly hampers the clinical translation progress of these nanosystems [ 220 , 232 ]. Conclusions and future perspectives Transitioning ferroptosis research from mere mapping of molecular mechanisms to clinical application urgently requires a unified conceptual framework centred on spatiotemporal dynamics. As revealed by this paper’s systematic analysis of tumour progression stages and TME locations, ferroptosis is highly dependent on specific biological contexts. Furthermore, the spatio-temporal attributes of ferroptosis directly define therapeutic windows. By precisely identifying specific temporal junctures (such as the EMT-driven tumour metastasis phase) or distinct spatial microenvironments (such as early cystine-depleted settings), the anti-tumour cell properties of ferroptosis can provide clear targets for clinical intervention. Moreover, viewed holistically, ferroptosis is not an isolated cell death event but the outcome of integrated multi-level regulatory mechanisms. For instance, the endoplasmic reticulum, lysosomes, and mitochondria collectively regulate ferroptosis, participating in cellular fate determination. Therefore, elucidating the interdependent relationships across different levels—tumour progression stages, organelle pathological states, and microenvironmental signals—is the core prerequisite for transitioning ferroptosis therapy from non-specific, blanket induction strategies towards coordinated precision death. This represents a critical breakthrough for advancing ferroptosis research towards clinical translation. However, the dynamic mechanisms by which diverse cell types within the TME regulate the spatiotemporal network of ferroptosis, and how they coordinate metabolic crosstalk, remain poorly understood. Although the cross-regulation between ferroptosis and other RCD types holds synergistic therapeutic potential, the clinical translation of such strategies requires validation through supportive biomarkers. Table 5 details the detection methods for known biomarkers. Table 5. Detection methods and clinical significance of ferroptosis biomarkers in different body fluids Biomarker Test sample Detection technology Correlation with ferroptosis Clinical significance Disease type Ref. 4-HNE Serum, tissue, cells Enzyme linked immunosorbent assay (ELISA), Immunohistochemistry (IHC) End products of lipid peroxidation. Therapeutic effect evaluation Squamous cell carcinoma of the oropharynx, BC, RCC [ 119 , 282 , 283 ] GPX4 Serum, tissue, cells qRT-PCR, western blot, IHC Maintain the antioxidant capacity of cells. Evaluation of the effect of inducing ferroptosis GC, TNBC, EC, CRC, liver cancer, PC, RCC, bladder cancer [ 25 , 105 , 284 , 285 ] LIP Serum, tissue, cells FerroOrange, phen green SK Ferroptosis launch icon Monitoring treatment response in iron overload GC, CRC, RCC, NSCLC, BC [ 15 , 284 , 286 , 287 ] SLC7A11 Tissue qRT-PCR, western blot, IHC Functional status of System xc − Predicting immunotherapy response GC, BC (estrogen receptor+), HCC, PCa, nasopharyngeal carcinoma [ 284 , 288 – 291 ] LPO Tissue, cells Fluorescent probe (C11-BODIPY), liquid chromatography-tandem mass spectrometry Ferroptosis execution marker Real-time monitoring of the ferroptosis process NSCLC, HCC, BC [ 292 , 293 ] GSH Plasma, tissue ELISA, fluorescent probe, GSH-GSSG ratio assay Antioxidant capacity Assessing sensitivity to ferroptosis RCC, CRC, TNBC [ 24 , 284 ], 294 – [ 296 ] FTH1 Serum ELISA Iron storage state Predicting treatment response to ferroptosis therapy and tumour prognosis RCC, DLBCL, etc. [ 74 , 297 – 299 ] Mitochondria ROS cells Fluorescent probe Mitochondrial oxidative stress Ferroptosis execution marker TNBC, HCC [ 124 , 300 – 303 ] MMP cells JC-1, Fluorescent staining, MitoView 650 Mitochondrial dysfunction Evaluating the Relationship Between Ferroptosis and Mitochondria TNBC, CRC [ 304 – 309 ] Exosomes miR-522 Plasma qRT-PCR Inhibiting ALOX15 to counteract ferroptosis Markers of chemotherapy resistance in GC. GC [ 197 ] Open in a new tab Moreover, the dual nature of ferroptosis warrants attention. Under specific circumstances, ferroptosis may exert pro-tumour effects through multiple pathways. For instance, ferroptosis in KRAS-mutant pancreatic cancer leads to the export of the oncogenic KRAS G12D protein, which promotes TAMs polarisation and thereby drives tumour progression [ 233 ]. Ferroptotic cells exhibit lower immunogenicity than necrotic cells and impede DCs maturation and antigen cross-presentation, thereby weakening adaptive antitumour immunity [ 171 ]. Furthermore, ferroptosis induces the release of danger signals (e.g., high-mobility group box 1) and the recruitment of immunosuppressive myeloid cells (e.g., MDSCs), establishing a tumour-growth-promoting immune microenvironment [ 234 , 235 ]. Consequently, ferroptosis-dependent tumour therapeutic strategies must account for the cell-type specificity, temporal control, and downstream immunological consequences of ferroptosis. At present, ferroptosis tumour therapies are broadly categorized into two strategies: first, searching for or designing conventional ferroptosis-inducing molecules, such as SRF, erastin, and their families; secondly, realizing precision delivery and controlled release of ferroptosis-inducing molecules by diving into advanced nanotechnology. The concise combination of the above two strategies not only presents high potential for ferroptosis-centred cancer therapeutics undergoing clinical translation, but nanomaterial-based delivery platforms still face a series of practical challenges, the overcoming of which is more urgent, including reproducible and scalable synthesis, formulation stability, predictable pharmacokinetics, and long-term biocompatibility. Hopefully overcoming these outstanding feasibility issues will eventually translate our experimental successes into clinic ready-markets and realize the full potentiality of ferroptosis-modulation therapies in cancer. In conclusion, to advance research and clinical translation of ferroptosis-dependent tumour therapies, the following priorities should be pursued: (1) Investigate the dynamic regulation of ferroptosis across tumour stages and cell types, alongside its interactions with immune cells. (2) Identify biomarkers predictive of treatment efficacy and immunological outcomes. (3) Establish reproducible nanodelivery standards and comprehensive safety evaluation systems. (4) Design mechanism-based combination strategies (e.g., ferroptosis with immunotherapy or other RCD-modulating synergies) and advance their clinical trials at the earliest opportunity. Through these four approaches, ferroptosis-based therapeutic strategies hold promise to reshape the treatment landscape and offer renewed hope for cancer patients. Abbreviations OH Hydroxyl radical 3'-UTR 3’ untranslated region 4EBP Eukaryotic translation initiation factor 4E-binding protein 4-HNE 4-hydroxynonenal 6-OH-FAD 6-hydroxy-FAD 7-DHC 7-dehydrocholesterol AA Arachidonic acid ACSL Long-chain acyl-CoA synthetase AKT Protein kinase B ALOX12 Arachidonate 12-lipoxygenase 12 S type ALOX15 Arachidonate 15- lipoxygenase APCs Antigen-presenting cells ARE Antioxidant response element ARNTL/BMAL1 Basic helix-loop-helix ARNT-like 1 ATF4 Activating transcription factor 4 ATG Autophagy-related protein BAP1 BRCA1-associated protein 1 BC Breast carcinoma BCa Bladder cancer BCL-2 B-cell lymphoma 2 BET Bromodomain and extra-terminal domain protein BH3 BCL-2 Homology domain 3 BH4 Tetrahydrobiopterin BRD4 Bromodomain protein 4 CA Cinnamaldehyde CAFs Cancer-associated fibroblasts CCN1 Cellular communication network factor 1 CDT Chemodynamic therapy CoA Coenzyme A COF Covalent organic framework COPS5 COP9 signalosome subunit 5 CoQ 10 Coenzyme Q 10 CoQ 10 H 2 Reduced coenzyme Q 10 CRC Colorectal cancer CRISPR Clustered regularly interspersed short palindromic repeats CS Chitosan CSCs Cancer stem cells CTH Cystathionine γ lyase Cys Cysteine DAMPs Damage-associated molecular patterns DCs Dendritic cells DEM Diethylmaleate DHA Dihydroartemisinin DHCR7 7-DHC reductase DHODH Dihydroorotate dehydrogenase DLBCL Diffuse large B-cell lymphoma DMT1 Divalent metal transporter 1 DNA Deoxyribonucleic acid Drp1 Dynamin-related protein 1 DSe Diselenide-linked levodopa EBV Epstein-Barr Virus EC Esophageal cancer ECM Extracellular matrix EGCG epigallocatechin gallate ELISA Enzyme linked immunosorbent assay EMCS ER-mitochondria contact sites EMT Epithelial-mesenchymal transition EPR Enhanced permeability and retention ER Endoplasmic reticulum ESCRT Endosomal sorting complex required for transport ETFA Electron transfer flavoprotein subunit alpha ETNK1 Ethanolamine kinase 1 FABP3/7 Fatty acid binding proteins 3 and 7 FAD Flavin adenine dinucleotide FADH 2 Reduced flavin adenine dinucleotide FAK Focal adhesion kinase FAO Fatty acid beta-oxidation FBXO3 F-box protein 3 Fc Ferrocene FDA Food and drug administration FDX1 Ferredoxin 1 Fe-S Iron-sulfur FINO2 (5α,8α)-8-(1,1-dimethylethyl)-3-methyl-1,2-dioxaspiro(4,5)decane-3-ethanol FOXK2 Forkhead box A2 FOXO3a Forkhead box protein O3a FPN Ferroportin FSP1 Ferroptosis suppressor protein 1 FTD/TPI Trifluridine/Tipiracil FTH1 Ferritin heavy chain 1 GBM Glioblastoma GC Gastric cancer GCH1 Guanosine triphosphate cyclohydrolase 1 GCL Glutamate-Cys ligase GOx Glucose oxidase GSDM Gasdermin GSH Glutathione GSS Glutathione synthetase H2A Histone 2 A H 2 S Hydrogen sulfide HA Hyaluronic acid HCC Hepatocellular carcinoma HCPG HA-CS@PtNP-GOx HIF Hypoxia-inducible factor HLF Hepatic leukemia factor HMOX1 Heme oxygenase 1 IDO Indoleamine 2, 3-dioxygenase IFN-Ⅰ Type Ⅰ interferon IFN-γ Interferon-gamma iFSP1 Inhibitor of ferroptosis suppressor protein 1 IHC Immunohistochemistry IKE Imidazole ketone erastin IL Interleukin iPLA2β Calcium-independent phospholipase A2β IPP Isopentenyl pyrophosphate KCTD12 Potassium channel tetramerization domain containing 12 KDM6A Lysine demethylase 6 A KEAP1 Kelch like ECH associated protein 1 L· Lipid radical LC3 Microtubule-associated protein 1 A/1B-light chain 3 LDH Lactate dehydrogenase LDs Lipid droplets LIP Labile iron pool LIP PCPO Liposome with phosphatidylcholine peroxide L-KYN L-Kynurenine lncRNA Long non-coding RNA LOH Lipid alcohols LOO· Lipid peroxyl radicals LOOH Lipid hydroperoxides LPCAT3 Lysophosphatidylcholine acyltransferase 3 LPO Lipid Peroxide m5C 5-methylcytosine MCⅠ Mitochondrial respiratory chain complex Ⅰ MDA Malondialdehyde MDSCs Myeloid-derived suppressor cells MLL4 Lysine methyltransferase 2B MMP Mitochondrial membrane potential MPO Myeloperoxidase mPTP Mitochondrial permeability transition pore MSL1 Male-specific lethal 1 mTOR Mammalian target of rapamycin mTORC1 Mammalian target of rapamycin complex 1 MUFAs Monounsaturated fatty acids MVD Mevalonate diphosphate decarboxylase NAD(P)H Nicotinamide adenine dinucleotide phosphate NCOA4 Nuclear receptor coactivator 4 NEDD4L NEDD4 like E3 ubiquitin protein ligase NFE2L2/Nrf2 Nuclear factor erythroid 2-related factor 2 NK Natural killer NSCLC Non-Small cell lung cancer NSUN2 NOP2/Sun RNA methyltransferase 2 OGT O-GlcNAc transferase OS Osteosarcoma OS Osteosarcoma OTUD5 Ovarian tumour domain-containing protein 5 PC Pancreatic cancer PCa Prostate cancer PCD programmed cell death PCIF1 Phosphorylated CTD interacting factor 1 PD-1 Programmed cell death protein 1 PDA Polydopamine PD-L1 Programmed cell death ligand 1 PDT Photodynamic therapy PE Phosphatidylethanolamine Pem Pemetrexed PGRMC1 Progesterone receptor membrane component 1 PHD Prolyl hydroxylase PI3K Phosphatidylinositol 3-kinase PLOHs Reduced phospholipid hydroperoxides PLOOHs Phospholipid hydroperoxides PLs Phospholipids PTMs Post-translational modifications PtNPs Platinum nanoparticles PTT Photothermal therapy PUFAs Polyunsaturated fatty acids RCC Renal cell carcinoma RCD Regulated cell death RETREG1/FAM134B Reticulophagy regulator 1 RIPK Receptor-interacting protein kinase R'OOH Hydroperoxides ROS Reactive oxygen species RSL3 RAS-selective-lethal-3 RTA Radical-trapping antioxidants SAS Sulfasalazine SCD Sickle cell disease SENP3 SUMO-specific peptidase 3 siMCT4 Monocarboxylic acid transporter protein 4 inhibiting siRNA SIRT1 Sirtuin 1 SLC1A1 Solute carrier family 1 member 1 SLC2A3 Solute carrier family 2 member 3 SLC3A2 Solute carrier family 3 member 2 SLC7A11 Solute carrier family 7 member 11 SQSTM1/p62 Sequestosome 1 Src Steroid receptor coactivator SRF Sorafenib STEAP3 Six-transmembrane epithelial antigen of the prostate 3 STING Stimulator of interferon genes STUB1 C-terminus of Hsc70-interacting protein System xc − Cystine/glutamate antiporter system TAMs Tumour associated macrophages TAX1BP1 Tax1 binding protein 1 TAZ Transcriptional coactivator with PDZ-binding motif TBK1 TANK binding kinase 1 Tf Transferrin TfR Transferrin receptor TGF Transforming growth factor tHB 3, 4, 5-trihydroxybenzaldehyde TIGIT T cell immune receptor with Ig and ITIM domains TILs Tumour infiltrating lymphocytes TME Tumour microenvironment TMEM192 Transmembrane protein 192 TNBC Triple-negative breast cancer TOM20 Translocase of outer mitochondrial membrane 20 TRAF6 Tumour necrosis factor receptor-associated factor 6 UCH Ubiquitin C-terminal hydrolases USP18 Ubiquitin-specific protease 18 YAP Yes-associated protein YTHDF2 YTH N6-methyladenosine RNA binding protein F2 Author contributions L.Z. Song, Y. Shu, T. Zhou and Y. Wang contributed to the manuscript writing and figure preparation, W.Z.Q. Zhang, Z. Zou, Y. Liao and C.L. Zhu designed the work, H.L. Zhang supervised the work. All authors have read and approved the article. All authors read and approved the final manuscript. Funding This study was funded by Shanghai Oriental Talent Top Project, Changhai Hospital Anesthesia Specialty Platform Construction Project and The National Natural Science Foundation of China (Grant No. 82572494). Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. This manuscript does not contain any studies with human participants or animals performed by any of the authors. Consent for publication Not applicable. This manuscript does not include details, images, or videos relating to an individual person. Competing interests The authors declare no competing interests. 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