Small molecules targeting regulated cell death for chronic kidney disease therapy.

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Learn more: PMC Disclaimer | PMC Copyright Notice J Pharm Anal . 2025 Aug 6;16(4):101427. doi: 10.1016/j.jpha.2025.101427 Search in PMC Search in PubMed View in NLM Catalog Add to search Small molecules targeting regulated cell death for chronic kidney disease therapy Wen-Kai Yu Wen-Kai Yu a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China Find articles by Wen-Kai Yu a, 1 , Qing-Ru Zhu Qing-Ru Zhu a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China Find articles by Qing-Ru Zhu a, 1 , Li Zhou Li Zhou a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China Find articles by Li Zhou a , Xin-Lei Shen Xin-Lei Shen a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China Find articles by Xin-Lei Shen a , Tian-Yang Cheng Tian-Yang Cheng b The Third Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310009, China Find articles by Tian-Yang Cheng b , Yi-Ni Bao Yi-Ni Bao a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China Find articles by Yi-Ni Bao a, ⁎⁎ , Gang Cao Gang Cao a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China Find articles by Gang Cao a, ⁎ Author information Article notes Copyright and License information a School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China b The Third Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310009, China ⁎ Corresponding author. [email protected] ⁎⁎ Corresponding author. [email protected] 1 Both authors contributed equally to this work. Received 2025 Mar 5; Revised 2025 Jun 30; Accepted 2025 Jul 31; Issue date 2026 Apr. © 2025 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMC Copyright notice PMCID: PMC13092030  PMID: 42011254 Abstract Chronic kidney disease (CKD) is a significant contributor to the global morbidity of non-communicable diseases and is predicted to become the fifth leading cause of death worldwide. However, effective treatments that directly target the underlying causes of CKD remain limited due to its complicated pathogenesis. Recent research has increasingly focused on elucidating the molecular mechanisms and identifying new therapeutic targets of CKD. In recent years, regulated cell death (RCD) has been highlighted as a central mechanism in the development and progression of CKD, suggesting that targeting specific RCD signaling pathways may offer effective strategies for CKD. Emerging research reveals that small molecules can effectively target different types of RCD in the context of CKD, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necroptosis. In this review, we summarize current understanding of the mechanism of RCD in CKD. Importantly, we emphasize the regulatory mechanism of small molecules on disturbed RCD to alleviate CKD. Taken together, this review enhances the comprehension of small molecules as modulators of RCD against CKD, which will provide new insights and potential avenues for CKD therapy. Graphical abstract Open in a new tab Highlights • Various RCD pathways, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necroptosis, contribute to renal dysfunction in CKD. • Small-molecule therapeutics targeting RCD pathways have shown potential in reducing kidney injury and inhibiting fibrotic signaling. • Clinical and translational research highlights RCD-targeted strategies as a promising approach to overcoming therapeutic limitations and advancing safer treatment options for CKD. 1. Introduction Chronic kidney disease (CKD) is an escalating global health concern, largely driven by aging populations and rising rates of metabolic disorders. By 2040, CKD is predicted to become the fifth leading cause of death worldwide, posing a major threat to public health [ 1 ]. The disease arises from a range of causes, including primary glomerulonephritis, hypertensive vascular damage, and diabetic nephropathy (DN) [ 2 ]. CKD development involves a multifactorial process, with contributors such as drug, age, obesity, infection, inflammation, immune reaction, hypertension, diet, genetics and diabetes, all of which collectively drive progressive kidney damage through tubulointerstitial atrophy, glomerulosclerosis, and fibrosis ( Fig. 1 ). As CKD progresses, patients commonly face complications including cardiovascular disease, anemia, and metabolic acidosis [ 3 ]. Without timely and effective intervention, CKD will inevitably progress to end-stage renal failure requiring dialysis or kidney transplantation. The global burden of CKD significantly reduces quality of life and imposes substantial economic costs on individuals and healthcare systems. Thus, identifying effective therapeutic strategies has become a pressing public health priority. Fig. 1. Open in a new tab Factors contributing to chronic kidney disease (CKD) and associated cell death pathways. CKD arises from a combination of factors, including aging, obesity, hypertension, genetics, diabetes, diet, immune responses, infections, nephrotoxic drugs, and inflammation. These stressors trigger several forms of cell death, such as apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necroptosis, all of which contribute to interstitial fibrosis, tubule atrophy, and glomerulosclerosis, eventually leading to CKD. Emerging evidence suggests that regulated cell death (RCD) plays a critical role in maintaining kidney homeostasis. Unlike accidental cell death, RCD is a form of cell death that driven by specific signaling pathways that can be modulated pharmacologically or genetically in CKD therapy. In 2018, the Nomenclature Committee on Cell Death (NCCD) updated its classification of RCD, identifying distinct subtypes based on morphology, biochemistry, and function. These include apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, necroptosis, mitochondrial permeability transition (MPT)-driven necrosis, ENTotic cell death, immunogenic cell death (ICD), lysosome-dependent cell death (LDCD), and parthanatos [ 4 ]. In CKD, pathological features such as tubular atrophy, glomerulosclerosis, and interstitial fibrosis are closely associated with dysregulated RCD pathways [ 5 , 6 ]. The predominant forms of RCD observed in CKD include apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necrosis, all of which dynamically interacting throughout disease progression ( Fig. 2 ). In early CKD, apoptosis and protective autophagy serve to preserve tissue integrity by removing damaged cells in a regulated and non-inflammatory manner. These processes are typically triggered by oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and Fas ligands, thus facilitating the clearance of damaged renal tubular epithelial cells (RTECs) and podocytes [ 7 ]. As CKD advances, a shift toward more inflammatory RCD forms occurs, including necroptosis, pyroptosis, and ferroptosis, which amplify inflammation and exacerbate renal injury. For example, in late-stage CKD, metabolic stress and iron overload trigger ferroptosis through lipid peroxidation and glutathione (GSH) depletion [ 8 ]. This transition from non-inflammatory to inflammatory cell death highlights the stage-dependent and dynamic nature of RCD in CKD. Apoptosis predominates in early stages, whereas mid-stage disease (stages 3 and 4) sees increased pyroptosis, mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) and gasdermin D (GSDMD), and necroptosis, involving receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) [ 9 ]. In advanced stages, ferroptosis becomes the dominant form of RCD due to suppression of GSH peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), while apoptosis further declines. Correspondingly, molecular markers evolve from early caspase-3 activation to mid-stage GSDMD and RIPK3 expression, and finally to GPX4 dysregulation in late disease [ 10 ]. Therapeutic strategies targeting RCD pathways offer potential stage-specific intervention. In early CKD, caspase inhibitors or B-cell lymphoma 2 (Bcl-2) modulators may effectively limit apoptosis. In contrast, late-stage disease may benefit more from agents that inhibit necrotic or inflammatory RCD forms, such as RIPK1 inhibitors or ferroptosis blockers. The contribution of RCD to nephron loss varies by cell type due to functional and metabolic differences. RTECs are particularly vulnerable to ferroptosis due to their reliance on iron-rich mitochondrial activity and elevated GPX4 expression [ 11 ]. Podocytes, as terminally differentiated glomerular cells, are prone to apoptosis under hyperglycemic conditions, which disrupt the Bcl-2-associated X protein (BAX)/Bcl-2 balance and activate mitochondrial pathways. They may also undergo pyroptosis in response to hyperglycemia or lipotoxicity, often via NLRP3 inflammasome activation. Mesangial cells, which contribute to glomerulosclerosis, commonly exhibit impaired autophagy along with increased apoptosis. Across all these cell types, RCD is intricately linked to chronic inflammation. CKD is characterized by persistent low-grade inflammation, with elevated levels of circulating cytokines such as interleukin-1β (IL-1β), IL-6, and TNF-α. These inflammatory mediators promote pyroptosis and necrosis, perpetuating a cycle of injury and fibrosis. Despite advances in CKD management, current therapies largely focus on controlling risk factors like hypertension and hyperglycemia using renin-angiotensin system (RAS) inhibitors and anti-inflammatory drugs. However, these treatments do not directly address renal fibrosis, the central driver of CKD progression. Anti-fibrotic drugs such as pirfenidone and pentoxifylline have limited efficacy due to poor bioavailability and systemic side effects [ 12 ]. Similarly, erythropoiesis-stimulating agents (ESAs) are constrained by dosing challenges and cardiovascular risks when hemoglobin levels exceed safe thresholds [ 13 ]. Promising new therapies are emerging, though clinical translation remains a challenge. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) and targeted nanotherapeutics, such as arginyl-glycyl-aspartic acid ((RGD)-modified mesenchymal stem cell exosomes, have demonstrated efficacy in preclinical models but require further validation in human trials. Natural antioxidants and herbal medicines exhibit anti-inflammatory and anti-fibrotic effects in animal studies, yet robust clinical data are lacking [ 14 ]. These limitations underscore the urgent need for novel, mechanistically targeted therapies. Recent studies have identified RCD modulation as a promising approach. Inhibiting ferroptosis, for example, by targeting GPX4, has shown protective effects in renal cells. The small molecule belnacasan (VX-765) inhibits both pyroptosis and ferroptosis by modulating upstream signaling, offering potential advantages in systemic safety compared to conventional treatments [ 15 ]. Additionally, targeted agents such as trimetallic nanoparticles (TMNPs) have shown efficacy in preventing acute kidney injury (AKI)-to-CKD transition through p38 mitogen activated protein family of kinase (p38 MAPK)-mediated ferroptosis inhibition [ 16 ]. A notable advancement involves small-molecule inhibitors of homeodomain-interacting protein kinase 2 (HIPK2), which disrupt its interaction with mothers against decapentaplegic homolog (Smad) family member 3 (Smad3), thereby blocking transforming growth factor (TGF)-β signaling, a key pathway in renal fibrosis. These inhibitors have demonstrated potent anti-fibrotic activity and favorable safety profiles in preclinical studies, supporting their progression into clinical trials. In conclusion, RCD pathways play a pivotal role in the onset and progression of CKD. Targeting RCD offers an effective therapeutic approach for CKD treatment. In this review, we summarize molecular mechanisms of key RCD subtypes implicated in CKD and highlights recent advances in small-molecule therapeutics ( Table 1 ) [17 – 57]. Fig. 2. Open in a new tab Key molecular mechanisms and interactions in regulated cell death (RCD). Several RCD pathways converge on mitochondrial damage, which plays a central role in initiating both apoptosis and autophagy. In parallel, caspase activity shapes the progression of necroptosis and pyroptosis. Despite their distinct mechanisms, all pathways ultimately lead to the permeabilization of the plasma membrane. (A) Apoptosis is driven by an imbalance in B-cell lymphoma 2 (Bcl-2) family proteins, leading to the activation of Bcl-2 homologues antagonist/killer (BAK) and Bcl-2-associated X protein (BAX). (B) Autophagy, in contrast, is characterized by the formation of autophagosomes that engulf damaged components. (C) Pyroptosis is triggered by the detection of cellular damage or infection through danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). (D) Ferroptosis is an iron-dependent form of RCD driven by lipid peroxidation of membrane phospholipids, which is counteracted by the system Xc − -glutathione (GSH)-GSH peroxidase (GPX4) axis and auxiliary antioxidant systems such as ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10). (E) Necroptosis is mediated by the receptor-interacting protein kinase 1 (RIPK1)-RIPK3-mixed lineage kinase domain-like protein (MLKL) signaling axis, leading to MLKL oligomerization. FADD: Fas-associated protein with death domain; IAP: inhibitor of apoptosis protein; TRADD: tumor necrosis factor (TNF) receptor-associated death domain protein; tBID: truncated Bcl-2 homology 3 domain (BH3) interacting domain death agonis; STAT3: signal transducer and activator of transcription 3; NF-κB: nuclear factor-κB; FOXO: forkhead box protein O; BCL-XL: B-cell lymphoma-extra large; APAF1: apoptotic protease-activating factor 1; Cyt c: cytochrome c; GSDME: gasdermin E; GSDME-NT: GSDME N-terminal domain; TLR4: Toll-like receptor 4; IL: interleukin; AMP: adenosine monophosphate; ATP: adenosine triphosphate; TRAIL: TNF-related apoptosis-inducing ligand; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; MAPK: mitogen-activated protein kinase; ERK 1/2: extracellular signal-regulated kinase 1/2; PARL: presenilin-associated rhomboid-like protein; BNIP3L: Bcl-2 interacting protein 3-like; NIX: Bcl2/adenovirus E1B 19 kDa-interacting protein 3-like; LC3: microtubule-associated protein 1 light chain 3; LOX: lipoxygenase; PUFA-PL: polyunsaturated fatty acid-phospholipid; ACSL4: acyl-CoA synthetase long-chain family member 4. Table 1. Regulatory small molecules in chronic kidney disease (CKD): active components and their pharmacological mechanisms of action. RCD Small molecules Category Pharmacological activity or mechanism of action Refs. Apoptosis Relaxin Biologic (peptide hormone) Activate the PI3K/Akt/endothelial nitric-oxide synthase signaling pathway to reduce apoptosis in renal interstitial fibrosis induced by acute r chronic renal failure [ 17 ] Ruxolitinib FDA-approved drug (JAK inhibitor) Inhibit STAT3 and Akt/mTOR/YAP pathways, alleviating apoptosis and renal fibrosis in UUO models [ 18 ] Isoliquiritigenin Phytochemical (flavonoid) Attenuate acute renal injury through suppressing oxidative stress, fibrosis and JAK2/STAT3 pathway in streptozotocin-induced diabetic rats [ 19 ] Sinomenine Phytochemical (alkaloid) Reduce renal cell apoptosis by regulating JAK2/STAT3/suppressor of cytokine signaling 1 pathway in diabetic kidney disease rats [ 20 ] Hydroxychloroquine FDA-approved drug (antimalarial/immunomodulatory) Inhibit PI3K/Akt and NF-κB signaling pathway [ 21 ] Ophiocordyceps lanpingensis Herbal extract (nucleoside/polysaccharide source) Inhibit MAPK pathway-medicated apoptosis [ 22 ] Levistolide A Phytochemical (dimeric phthalide) Deregulate Ras, cyclic AMP response element-binding protein, TGF-β1/Smad and MAPK signaling pathways [ 23 ] Platelet-rich plasma Biologic (cellular therapy) Reduce the expression of caspace-3 and immune response [ 24 ] Geraniol Phytochemical (monoterpenoid) Regulate the conduction of Wnt/β-catenin and peroxisome proliferator-activated receptor gamma signals [ 25 ] Cur Phytochemical (polyphenol) Decrease apoptosis signaling proteins (cleaved caspase-3 and cleaved caspase-12) in the kidneys of non-alcoholic steatohepatitis rats [ 26 ] Autophagy Dihydromyricetin Phytochemical (flavonol) Inhibit miR-155–5p/PTEN and PI3K/Akt/mTOR signaling pathway in DN [ 27 ] Ginsenoside Rb1 Phytochemical (triterpene saponin) Regulate AMPK/mTOR, Akt independent and p38/ERK signaling pathways, and ultimately alleviate renal fibrosis [ 28 ] Rhein Phytochemical (anthraquinone derivative) Rrgulate AMPK/mTOR, p38/ERK, and Akt independent signaling pathways [ 29 ] Geniposide Phytochemical (iridoid glycoside) Induce autophagy by activating AMPK activity and inhibiting Akt activity [ 30 ] Tripterygium glycoside Phytochemical (diterpene lactone/triterpene saponin mix) Inhibit renal fibrosis by downregulating mTOR phosphorylation and enhancing autophagy [ 31 ] Triptolide Phytochemical (epoxy diterpene lactone) Regulate miR-141–3p/PTEN/Akt/mTOR pathway to restore autophagy [ 32 ] Cordyceps cicadae Fungal extract (nucleoside/polysaccharide source) Target the PI3K/mTOR-mediated autophagy pathway [ 33 ] Metformin FDA-approved drug (biguanide antidiabetic) Activate mitochondrial autophagy through AMPK-Pink1-Parkin pathway [ 34 ] Pyroptosis Anakinra Biologic (IL-1 receptor antagonist) A selective IL-1β receptor antagonist, which is an important effector molecule downstream of the pyroptosis pathway [ 35 ] Canakinumab Biologic (monoclonal antibody) A specific human monoclonal antibody targeted against IL-1β and can directly targets IL-1β, thereby reducing renal fibrosis [ 36 ] Cucurbitacin B Phytochemical (tetracyclic triterpenoid) Directly bind to TLR4, trigger the activation of NLRP3 inflammatory body, lead to the cleavage of GSDMD [ 37 ] BAY11-7082 Experimental compound (NF-κB inhibitor) It is a NF-κB inhibitor that reduces the activation of the NLRP3 inflammasome and reduces pyroptosis by inhibiting the activation of NF-κB [ 38 ] Melatonin Endogenous hormone (indoleamine) Reduce the activation of NLRP3 inflammator and reduce pyroptosis by reducing oxidative stress [ 39 ] Berberine Phytochemical (alkaloid) Inhibit the activation of NLRP3 inflammasome by activating AMPK and reduce pyroptosis [ 40 ] 4-Phenylbutyrate FDA-approved drug (anti-urea cycle disorders) Inhibit the ER stress-induced apoptosis, restore the number of tubular cells, and restore tubular integrity [ 41 ] Ferroptosis Ginkgolide B Phytochemical (diterpene lactone) Inhibition of ubiquitination degradation of GPX4 alleviates lipid metabolism disorders, thereby alleviating ferroptosis and renal fibrosis [ 42 ] Tectorigenin Phytochemical (isoflavone) Inhibiting Smad3 phosphorylation and suppressing the expression of NOX4 in the UUO mouse model, thus blocking Smad3-mediated ferroptosis [ 43 ] Fisetin Phytochemical (flavonol) Inhibit ACSL4-mediated renal tubular ferroptosis [ 44 ] Gastrodin Phytochemical (phenolic glycoside) Inhibit ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway [ 45 ] Salidroside Phytochemical (phenylethanol glycoside) Reverse the expression of SLC7A11 and GPX4 in SAMP8 mice [ 46 ] Nobiletin Phytochemical (flavone) Reduce the expression of SLC7A11 and transferrin receptor protein 1 and inhibit ferroptosis in UUO mouse models [ 47 ] Puerarin Phytochemical (isoflavone) Inhibit NOX4 and Nrf2/HO-1 signaling and increase the expression of SLC7A11 and GPX4 [ 48 ] Tocilizumab mimotope Biologic-derived peptide Increase GPX4 and ferritin levels, which may be related to inhibit IL-6/ERK signaling pathway and ferroptosis, downregulate pro-fibrotic protein [ 49 ] DFO mesylate FDA-approved drug (iron chelator) Inhibit ferroptosis by chelating iron ions within cells and reducing iron-dependent lipid peroxidation [ 50 ] N -acetylcysteine FDA-approved drug (antioxidant) An antioxidant that promotes the synthesis of GSH by providing cysteine, thereby enhancing the antioxidant capacity and inhibiting ferroptosis [ 51 ] Vitexin Phytochemical (flavonoid) Inhibit RTEC ferroptosis by blocking Nrf2 activation [ 52 ] Necroptosis Nec-1 Experimental compound (necrosis inhibitor) Inhibit the kinase activity of RIPK1 and block necrosome formation [ 53 ] TAK-632 Experimental compound (kinase inhibitor) A Raf kinase inhibitor that can simultaneously inhibit RIPK1 and RIPK3, activity and block necroptosis [ 54 ] 6,7-Dihydroxycoumarin Phytochemical (coumarin derivative) A MLKL inhibitor that can inhibit necroptosis by binding to the pseudo-kinase domain of MLKL, preventing oligomerization and membrane translocation of MLKL [ 55 ] KW-2449 Experimental compound (kinase inhibitor) A multi-target kinase inhibitor that targets RIPK1 and supposes necroptosis [ 56 ] RGMb Protein (repulsive guidance molecule) Reduce MLKL and inhibit renal tubular cell necrotic apoptosis [ 57 ] Open in a new tab RCD: regulated cell death; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; FDA: U.S. Food and Drug Administration; JAK: janus kinase; STAT3: signal transducer and activator of transcription 3; mTOR: mammalian target of rapamycin; YAP: yes-associated protein; UUO: unilateral ureteral obstruction; AMPK: adenosine monophosphate (AMP)-activated protein kinase; BAX: B-cell lymphoma 2 (Bcl-2)-associated X protein; NF-κB: nuclear factor-κB; MAPK: mitogen-activated protein kinase; TGF-β1: transforming growth factor-β1; Smad: mothers against decapentaplegic homolog; Cur: curcumin; ERK: extracellular signal-regulated kinase; PTEN: phosphatase and tensin homolog; DN: diabetic nephropathy; IL-1: interleukin-1; TLR4: Toll-like receptor 4; NLRP3: nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3; GSDMD: gasdermin D; ER: endoplasmic reticulum; GPX4: glutathione (GSH) peroxidase 4; NOX: nadph oxidase; ACSL4: acyl-coa synthetase long-chain family member 4; SIRT1: sirtuin 1; FOXO3A: forkhead box protein O3A; SAMP8: senescence-accelerated mouse prone 8; SLC7A11: solute carrier family 7 member 11; SAMP8: senescence-accelerated mouse prone 8; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase-1; DFO: deferoxamine; RTEC: renal tubular epithelial cell; Nec-1: necrostatin-1; RIPK1: receptor-interacting protein kinase 1; MLKL: mixed lineage kinase domain-like protein. 2. The key signaling pathways of RCD 2.1. The key signaling pathways of apoptosis Apoptosis, a caspase-dependent form of programmed cell death, mediates approximately 90% of cellular turnover and is a major contributor to the transition from AKI to CKD. By eliminating essential cell types such as RTECs, mesangial cells, and podocytes, apoptosis promotes structural damage and fibrotic remodeling in the kidney [ 58 ]. At the molecular level, caspase-3 serves as the primary executioner of apoptotic signaling. Formed through dimerization of its 17 and 12 kDa subunits, activated caspase-3 cleaves key substrates including poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), impairing DNA repair, cytoskeletal organization, and membrane integrity [ 59 ]. Apoptotic signals are further amplified by TNF superfamily cytokines, which engage death receptors and activate downstream components such as RIPK1. Post-translational modifications, including palmitoylation via the transferase aspartate-histidine-histidine-cysteine 5 (Dhhc5) and K63-linked ubiquitination, enhance RIPK1's activity by promoting self-association and membrane affinity, thereby intensifying apoptotic signaling. Therapeutically, modulation of apoptotic pathways is an emerging therapeutic strategy. For example, Bcl-2 homology 3 domain (BH3) mimetics and inhibitors of anti-apoptotic Bcl-2 family proteins exhibit synergistic effects when combined with ferroptosis inducers [ 60 ]. The tumor suppressor p53 enhances apoptosis by upregulating pro-apoptotic proteins and suppressing Bcl-2. It also sensitizes cells to ferroptosis by downregulating SLC7A11, a key component of cystine uptake and GSH synthesis [ 61 ]. Recent studies have identified several novel molecular mediators involved in apoptotic signaling in CKD. One key player is voltage-dependent anion channel 2 (VDAC2), which regulates apoptosis by promoting BAX oligomerization, increasing mitochondrial membrane permeability, and facilitating the release of cytochrome c (Cyt c) [ 62 ]. In models kidney injury induced by high-fat diets, palmitoylation of the fatty acid transporter CD36 activates the c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) signaling pathways, thereby inducing RTEC apoptosis and accelerating fibrosis [ 63 ]. Recent single-cell RNA sequencing studies have identified naked cuticle 2 (NKD2) as a key regulator of myofibroblast activity in renal fibrosis. By modulating the Wnt/β-catenin pathway, NKD2 promotes the apoptosis of damaged cells and prevents their pathological accumulation. This dual function highlights NKD2 as a promising therapeutic target for mitigating CKD progression [ 64 ]. Non-coding RNAs (ncRNAs) are genome transcripts that do not translate into proteins, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). In CKD, ncRNAs have emerged as important regulators of apoptosis-related pathways. For example, inhibition of miR-17-5p has been shown to alleviate high glucose (HG)-induced mesangial cell apoptosis and renal fibrosis by targeting kinesin family member 23 (KIF23) and activating Wnt/β-catenin pathway [ 65 ]. miRNA-21 (miR-21), a well-characterized oncogenic miRNA, modulates apoptosis and fibrosis by targeting phosphatase and tensin homolog (PTEN) and activating the protein kinase B (Akt) pathway. While promoting cell survival under physiological conditions, its pathological overexpression in AKI, DN, and fibrosis dysregulates RTEC apoptosis. Similarly, Ma et al. [ 66 ] demonstrated that lncRNA nuclear enriched assistant transcript 1 (Neat1) competitively binds to miR-129-5p and prevents miR-129-5p from downregulating Fas-associated protein with death domain (FADD), caspase-8, and caspase-3, which in turn facilitates RTEC apoptosis and promotes the progression from AKI to CKD. In another study, the lncRNA LOC105374325 was found to be significantly upregulated in the podocytes of patients with focal segmental glomerulosclerosis (FSGS). By binding competitively to miR-34c and miR-196a/b, LOC105374325 can promote podocyte apoptosis and driving FSGS progression [ 67 ]. Conversely, some ncRNAs appear to play protective roles. For example, circAKT3 has been shown to reduce apoptosis in DN by regulating the miR-296-3p/E-cadherin pathway, thereby inhibit mesangial cell death and extracellular matrix (ECM) accumulation [ 68 ]. In summary, targeting apoptotic signaling pathways offers a novel and potentially effective strategy to delay the advancement of CKD. 2.2. The key signaling pathways of autophagy-dependent cell death Autophagy is an essential cellular mechanism that maintains homeostasis by removing damaged or unnecessary components, especially under stress conditions. The canonical autophagy pathway involves the formation of double-membraned autophagosomes, driven by key autophagy-related proteins (ATGs) such as ATG5, ATG7, and microtubule-associated protein 1 light chain 3 (LC3), which deliver cellular debris to lysosomes for degradation [ 69 ]. In addition to this classical route, non-canonical pathways such as LC3-associated phagocytosis (LAP) have been identified. These alternative mechanisms bypass certain ATG-dependent steps and rely on distinct membrane sources to target specific substrates [ 70 ]. Under normal physiological conditions, autophagy plays a protective role by recycling cellular components to maintain metabolic homeostasis. However, when cellular stress is prolonged or severe, autophagy may become dysregulated. In such cases, the excessive or impaired autophagy can lead to autophagy-dependent cell death, which characterized by mitochondrial dysfunction and the accumulation of damaged organelles. Dying cells undergoing autophagy-dependent cell death often exhibit more numerous and enlarged autophagic vesicles compared to those under nutrient deprivation, suggesting that a pathological shift from a protective to a harmful process [ 71 ]. Recent evidence highlights the dual role of autophagy in CKD, with its effects varying by cell type and disease stage. In the early phases of renal injury, autophagy facilitates cellular repair and offers protection. However, persistent or excessive autophagy may disrupt kidney integrity and contribute to CKD. For example, in a unilateral ureteral obstruction (UUO) mice model, sustained autophagy in proximal tubular cells has been shown to promote renal fibrosis by accelerating apoptosis, tubular atrophy, nephron loss, and interstitial macrophage infiltration. Notably, these pathological changes were mitigated by pharmacological inhibition or genetic deletion of ATG7, suggesting persistent autophagy as a driver of renal fibrosis in UUO [ 72 ]. Conversely, autophagy appears to play a protective role on both sides of the glomerular filtration barrier in DN. HG-induced autophagy deficiency in podocytes significantly decreased cell viability and increased apoptosis. Similarly, the deletion of ATG5 in glomerular endothelial cells led to capillary rarefaction and exacerbated DN progression. These findings suggest that maintaining autophagic activity in podocytes and glomerular endothelial cells is a promising therapeutic strategy for DN [ 73 ]. As noted above, autophagy plays diverse roles in different cell types during CKD. Nanoparticle (NP) based drug delivery systems, cell targeting peptides (CTPs), and cell-penetrating peptides (CPPs) have emerged as promising targeted therapies for CKD [ 74 ]. These approaches allow for the selective delivery of therapeutic small molecules to specific cell types, thus promoting its protective functions while inhibiting its harmful effects. Beyond its role in cell survival, autophagy also regulates fibrotic signaling. It facilitates the degradation of mature TGF-β1, reducing profibrotic signaling and protecting against tubulointerstitial fibrosis, especially in UUO models. In autophagy-deficient models, such as LC3 knockout and beclin1 heterozygous mice, the elevated TGF-β1 expression are accompanied by increased collagen I deposition, suggesting that autophagy acts as a feedback mechanism to inhibit fibrosis [ 75 ]. Interestingly, TGF-β1 can induce autophagy, which in turn facilitates its own degradation, forming a self-regulating loop. Additional studies show that Wnt-1 inducible signaling pathway-1 (WISP-1), a profibrotic mediator, activates autophagy in RTECs in response to TGF-β1 signaling. In forkhead box D1 (FOXD1)-derived stromal cells, autophagy further contributes to antifibrotic responses by inhibiting the TGF-β1/Smad4 pathway through modulation of the NLRP3 inflammasome. Collectively, these findings position autophagy as a key regulator of both cell survival and fibrotic progression in CKD. Its context-dependent effects across different renal cell types highlight autophagy-dependent cell death as a promising therapeutic target. 2.3. The key signaling pathways of regulated necrosis Regulated necrosis is a form of programmed cell death marked by the rupture of the cell membrane, leading to the release of intracellular contents and triggering inflammatory responses. Unlike passive necrosis, these pathways are tightly controlled by specific molecular signaling. Pyroptosis, ferroptosis, and necroptosis are three types of regulated necrosis that have been extensively studied, each of which act through distinct mechanisms and contribute to the development and progression of CKD. Mechanistically, pyroptosis is initiated by the activation of inflammatosomes and is primarily regulated by caspase-1, caspase-4, caspase-5, and caspase-11. Ferroptosis is driven by lipid peroxidation and relies on the activity of GPX4. Necroptosis, often referred to as necrotic apoptosis, is governed by the RIPK1/RIPK3/MLKL signaling axis. These forms of regulated necrosis also play distinct roles in maintaining renal homeostasis. Pyroptosis, driven by GSDMD channel activation, can facilitate the clearance of infected or damaged cells, thereby preserving the structural integrity of renal tubules and enabling the replacement of aging cells [ 76 ]. As a highly inflammatory process, pyroptosis is also essential for defending the kidney against fungal, bacterial, and viral pathogens. Ferroptosis contributes to renal function in different ways. The kidney is especially prone to ferroptosis due to its high metabolic rate and elevated expression of lipoxygenases (LOXs), which promote lipid peroxidation [ 77 ]. This vulnerability makes it a key organ for studying ferroptosis in vivo . Under physiological conditions, ferroptosis supports iron regulation in the proximal tubules, particularly through acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid metabolism [ 78 ]. Necroptosis plays a more prominent role during renal development and in response to cellular stress. In the developing kidney, necroptosis contributes to tissue morphogenesis by selectively eliminating specific cell populations, thereby precisely shaping the architecture of nephrons and collecting ducts. In adulthood, necroptosis can facilitate the clearance of damaged and senescent cells, thus preventing dysfunctional cells accumulation and maintaining renal function. Additionally, it also promotes epithelial cell turnover, contributing to the renewal and integrity of renal tissue [ 79 ]. 2.3.1. The key signaling pathways of pyroptosis Pyroptosis, an inflammatory form of programmed cell death, has emerged as a significant driver in the progression of CKD. Mechanistically, pyroptosis is mediated through canonical (caspase-1-dependent) and noncanonical (caspase-1-independent) pathways. In the canonical pathway, extracellular signals such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) activate the NLRP3 inflammasome, triggering caspase-1 auto-cleavage and activation. The active caspase-1 then cleaves GSDMD, leading to the formation of membrane pores. This pore formation causes cell lysis and the release of proinflammatory cytokines, such as IL-1β and IL-18, thereby exaggerating tissue damage and promoting renal fibrosis [ 80 ]. In CKD, pathological stimuli such as oxidative stress, hyperglycemia, and advanced glycation end products are known to activate the NLRP3 inflammasome, which initiates a cascade of inflammatory responses and amplifies renal inflammation [ 81 ]. Notably, NLRP3 inflammasome activation is especially pronounced in DN, where chronic hyperglycemia drives excessive production of IL-1β and IL-18, contributing to fibrosis and renal functional decline. Emerging evidence also highlights the interplay between different members of the gasdermin family in kidney injury. Both GSDMD and GSDME are implicated in the transition from AKI to CKD. GSDME contributes to tubular cell death, which in turn activates a GSDMD-driven inflammatory response. Simultaneously targeting GSDMD and GSDME may offer a strategy to slow this pathological progression. Granzyme B (GZMB), a protease secreted by cytotoxic T and natural killer cells, can cleave both GSDMD and GSDME, thereby inducing pyroptosis. Inhibiting GZMB has been shown to reduce pyroptotic cell death, suggesting its potential as a therapeutic target [ 82 ]. Beyond the canonical pathway, pyroptosis can also occur through noncanonical mechanisms. Caspase-4, caspase-5, and caspase-11 can directly cleave GSDMD, releasing an active fragment that forms pores in the plasma membrane. These pathways have been linked to podocyte loss in DN and can induce pyroptosis in immune cells independently of IL-1β release [ 83 ]. Regulatory mechanisms such as epigenetic and post-translational modifications further influence pyroptotic activity. DNA methylation and histone modifications affect the expression of inflammasome-related genes, while protein ubiquitination and phosphorylation modulate the function of key pyroptosis mediators. Targeting these modifications provides new therapeutic avenues. For example, the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) has been shown to suppress NLRP3 expression and reduce inflammation in experimental CKD models [ 84 ]. In conclusion, pyroptosis plays a central role in the pathogenesis of CKD by driving inflammation, fibrosis, and functional decline. 2.3.2. The key signaling pathways of ferroptosis Ferroptosis is an iron-dependent form of RCD driven by lipid peroxidation, first identified in 2012 [ 85 ]. This process is characterized by the accumulation of lipid peroxides and diminished GPX4 activity, leading to redox imbalance and membrane damage. In CKD, several signaling pathways contribute to disease progression by promoting ferroptosis. Among these, the system Xc − -GSH-GPX4 axis plays a central role. System Xc − facilitates the uptake of cysteine, a precursor for GSH synthesis. GPX4, in turn, uses GSH to neutralize lipid peroxides and maintain redox balance [ 86 ]. Inhibition of system Xc − or inactivation of GPX4 renders cells susceptible to iron-mediated oxidative stress, resulting in lipid peroxidation, mitochondrial dysfunction, and AKI [ 87 ]. Beyond this canonical pathway, ferroptosis is also regulated by lipid metabolic enzymes. For example, ACSL4 and lysophosphatidylcholine acyltransferase 3 (LPCAT3) promote the incorporation of polyunsaturated fatty acids (PUFAs) into membrane phospholipids (PLs), further increasing susceptibility to peroxidation [ 88 ]. Notably, ACSL4 has been proposed as a biomarker of ferroptosis, and its inhibition has been shown to reduce key peroxidation intermediates, such as arachidonoyl- and adrenoyl-phosphatidylethanolamines, thereby alleviating fibrotic kidney injury [ 89 ]. An alternative regulatory mechanism involves ferroptosis suppressor protein 1 (FSP1), which functions independently of GSH. FSP1 converts coenzyme Q10 into a lipid-soluble antioxidant that halts lipid peroxidation and prevents ferroptotic cell death [ 90 ]. In renal tubular cells, FSP1 deficiency exacerbates oxidative damage, whereas its overexpression or coenzyme Q10 (CoQ10) supplementation has been shown to protect against ischemia-reperfusion (I/R) injury [ 91 ]. The kidney's high iron content and oxygen demand make it particularly vulnerable to ferroptosis. In CKD, lipid accumulation and impaired lipid metabolism can activate innate immune responses, disrupt mitochondrial function, and promote fibrosis. These effects are further intensified in DN, where hyperglycemia drives iron overload, weakens antioxidant defenses such as GPX4, and increases lipid peroxidation via reactive oxygen species (ROS). In summary, ferroptosis contributes to CKD pathogenesis through multiple interconnected pathways involving oxidative stress, lipid dysregulation, and impaired redox control. 2.3.3. The key signaling pathways of necroptosis Necroptosis a regulated form of programmed cell death that shares molecular features with apoptosis but results in morphological changes characteristic of necrosis. Unlike apoptotic cells, which undergo controlled shrinkage while preserving membrane integrity, cells undergoing necroptosis swell rapidly and adopt a distinctive balloon-like morphology before rupturing. Necroptosis is orchestrated by three key proteins, including RIPK1, RIPK3, and MLKL. Upon activation, RIPK1 and RIPK3 phosphorylate MLKL, which then translocate to the cell membrane. Subsequently, phosphorylated MLKL forms pores that disrupt the membrane, leading to cell death [ 92 ]. Necroptosis is typically initiated by signals from TNF receptor 1 (TNFR1), Toll-like receptors (TLRs), and interferon (IFN) receptors (IFNRs), which recruit RIPK1/RIPK3 to trigger the pathway [ 93 ]. Interestingly, caspase-8 plays a pivotal role in determining the mode of cell death. Caspase-8 promotes apoptosis, but its inhibition shifts cell fate toward necroptosis by enabling RIPK1/RIPK3-dependent necrosome assembly and MLKL activation [ 94 ]. Alternative pathways have also been identified. For instance, inhibition of fibroblast growth factor receptor 2 (FGFR2) can trigger MLKL activation independently of RIPK1 and RIPK3 via the macrophage stimulating 1 (MST1)-neurofibromin 2 (NF2)-yes-associated protein (YAP) axis and suppression of Hippo signaling. Preclinical studies highlight the pathological relevance of necroptosis in kidney disease. Deletion of RIPK3 protects against sepsis-induced AKI, while simultaneous deletion of RIPK3 and MLKL mitigates renal damage caused by oxalate crystal deposition [ 95 ]. These findings underscore the contribution of necroptosis to kidney injury and inflammation. In the context of CKD, necroptosis has been increasingly recognized as a key mechanism in disease progression. Elevated levels of RIPK1, RIPK3, and MLKL in CKD patients correlate with ECM accumulation and renal fibrosis. This may be partly due to the mitochondrial localization of RIPK3 and MLKL, which disrupts mitochondrial function and exacerbates renal injury [ 96 ]. Persistent pathological stimuli in CKD, such as oxidative stress, chronic inflammation, and metabolic imbalances, can activate necroptotic signaling. For example, persistent inflammation releases inflammatory factors such as TNF-α, which in turn activate the RIPK1/RIPK3/MLKL signaling to trigger necroptosis [ 97 ]. Necroptosis appears to be particularly active during CKD stages 2 to 3a, where it contributes directly to tubulointerstitial fibrosis, a key driver of CKD progression [ 98 ]. These findings suggest that early intervention targeting necroptosis may offer new opportunity to prevent AKI and delay CKD progression. 2.4. Crosstalk between RCD subroutines The regulation of distinct forms of RCD constitutes a complex and interconnected network that plays a central role in determining cellular fate. These pathways often share molecular components and signaling mechanisms, facilitating extensive crosstalk that can amplify or suppress specific death modalities depending on the cellular stressor, environmental context, or disease state. A single stimulus may simultaneously activate multiple RCD pathways. For instance, in non-renal systems, certain pathogens such as viruses, have been shown to trigger pyroptosis, apoptosis, and necroptosis concurrently in innate immune cells, a coordinated process termed PANoptosis. This response is mediated by PANoptosome, multiprotein complexes containing RIPK1, RIPK3, and ZBP1 [ 99 ]. Caspase-6 has recently been identified as a regulator of Z-DNA binding protein 1 (ZBP1)-mediated PANoptosis and NLRP3 inflammasome activation, independent of its proteolytic activity. Although elevated caspase-6 levels have been observed in kidney injury models, its specific role in renal pathology remains unclear [ 100 ]. When multiple RCD pathways are simultaneously activated, inhibition of one pathway often fails to prevent cell death and instead shifts its modality [ 101 ]. For example, MLKL-deficient fibroblasts are resistant to necroptosis but become susceptible to ferroptosis during cystine deprivation. Conversely, ACSL4-deficient cells, which are protected from ferroptosis, show heightened sensitivity to TNF-induced necroptosis when caspases are inhibited [ 102 ]. Similarly, broad-spectrum caspase inhibition with zVAD-fmk can suppress apoptosis but promote necroptosis, often exacerbating overall cell death [ 103 ]. Many RCD regulators exhibit functional plasticity by participating in multiple death pathways. The tumor suppressor p53, for instance, promotes apoptosis by activating pro-apoptotic Bcl-2 proteins and concurrently inhibits ferroptosis by upregulating the cystine transporter SLC7A11. Loss of p53 disrupts this balance, increasing ferroptotic vulnerability through impaired cystine uptake. Caspases also serve as pivotal nodes in RCD crosstalk [ 104 ]. Caspase-3 can induce pyroptosis via GSDME cleavage, whereas caspase-1 can activate apoptotic caspases under certain conditions [ 105 ]. Autophagy exemplifies the dynamic interplay among RCD pathways through its reciprocal regulation with apoptosis, pyroptosis, and necroptosis. It often shares upstream triggers and regulatory components with apoptosis, enabling mutual modulation. For example, Beclin-1, a core autophagy protein, binds Bcl-2 to regulate the balance between autophagy and apoptosis [ 106 ]. Pathologically elevated autophagy induced by farnesoid X receptor (FXR) deficiency or transcription factor EB (TFEB) overexpression can trigger apoptosis in RTECs, thereby exacerbating renal injury in I/R and adenine diet-induced models of CKD [ 107 ]. Additionally, autophagy modulates pyroptosis by regulating NLRP3 inflammasome activation. Its inhibition has been shown to suppress NLRP3-mediated pyroptosis in RTECs and prevent progression of hyperuricemic nephropathy. Context-dependent shifts in RCD pathways further illustrate their interconnectedness. Under nutrient deprivation, autophagic cell death is typically favored while necroptosis is suppressed [ 108 ]. In contrast, RIPK1, a central necroptosis regulator, can inhibit autophagy via mammalian target of rapamycin (mTOR) activation. Notably, ferroptosis also engages in bidirectional crosstalk with other RCD mechanisms. GPX4 inhibition not only triggers ferroptosis but also activates the JNK-p53-apoptosis axis, while lipid peroxidation products promote necroptosis through RIPK1 modification [ 109 ]. A similar interdependence exists between necroptosis and pyroptosis. MLKL-driven membrane disruption during necroptosis releases DAMPs that activate the NLRP3 inflammasome, thereby enhancing pyroptosis. This positive feedback loop is attenuated by pyroptosis-induced caspase-8 activation, which suppresses necroptosis via RIPK3 degradation [ 110 ]. Collectively, these interactions highlight the intricate and dynamic crosstalk among RCD pathways. Disruption of this regulatory network contributes substantially to the pathogenesis and progression of CKD. 3. Targeting apoptosis with small molecules in CKD Fusidic acid, a U.S. Food and Drug Administration (FDA) approved antibiotic with anti-inflammatory and anti-fibrotic properties, has been shown to attenuate renal fibrosis by inhibiting tumor protein 53 regulating kinase (TP53RK)/baculoviral IAP repeat containing 5 (BIRC5) signal pathway. In UUO model, a 10 mg/kg dose demonstrated significant therapeutic efficacy [ 111 ]. Similarly, the anticancer agent Ym-155, currently in phase II clinical trials, mitigates renal fibrosis by targeting BIRC5 and suppressing the phosphoinositide 3-kinase (PI3K)/Akt and MAPK pathways [ 112 ]. Both fusidic acid and Ym-155 can exert effects via apoptosis-related mechanisms, highlighting apoptosis a critical therapeutic target in renal fibrosis. Natural compounds such as resveratrol and curcumin (Cur) also have a potential therapeutic effect in CKD. Resveratrol promotes apoptosis through sirtuin 1 (SIRT1) activation, while Cur inhibits the NF-κB pathway, thereby reducing both inflammation and apoptosis. These effects have been validated in models such as 5/6 nephrectomized rats and I/R injury [ 113 ]. Rosmarinic acid (RA), a widely distributed polyphenol with potent antioxidant and anti-inflammatory activity, exhibits renoprotective effects. However, its clinical application is hindered by poor water solubility, low bioavailability, and physiological instability. NP-based delivery systems have been developed to overcome these limitations, enhancing RA's stability and bioavailability. Compared to unmodified RA, these nanoparticles (NPs) show superior in vitro antioxidant and anti-apoptotic activity and improve renal function, reduce oxidative stress and inflammation, promote tissue repair, and decrease tubular epithelial cell apoptosis in vivo [ 114 ]. In another study, 16 bioactive compounds were isolated from Daphne genkwa , a plant with known anti-fibrotic effects. Among these, compound daphnepedunin A (DA) exhibited the strongest anti-fibrotic activity, surpassing pirfenidone, an approved treatment. DA alleviates renal fibrosis by targeting cell division control protein 42 homolog (CDC42) and inhibiting the β-catenin signaling pathway. This mechanism was confirmed through CDC42 pull-down assays, cellular thermal shift assays, surface plasmon resonance, and rescue experiments. Molecular docking and residue mutation studies identified Leu119 and Lys128 as critical residues on CDC42. Correlations between CDC42 expression and fibrosis markers such as alpha-smooth muscle actin (α-SMA), collagen I/III, and fibronectin further underscore DA's therapeutic potential [ 115 ]. The findings position DA as a promising natural lead compound for anti-fibrotic drug development. Quercetin, another natural compound, has demonstrated significant renoprotective activity. In diabetic rat models, 50 mg/kg quercetin alleviated inflammation and fibrosis by modulating macrophage polarization. Specifically, it inhibited M1 polarization and attenuated fibrosis by suppressing the TLR4/myeloid differentiation primary response gene 88 (MyD88) pathways and downstream NF-κB and IFN regulatory factor 5 (IRF5) signaling. In glomerulosclerosis models, quercetin significantly improved serum creatinine (SCR) and blood urea nitrogen (BUN) levels, reduced proteinuria, inhibited inflammatory infiltration, promoted apoptosis, and corrected lipid metabolism. Phase II clinical trials further suggest that quercetin may protect against contrast-induced nephropathy [ 116 ]. Desloratadine, an FDA-approved antihistamine with anticancer potential, has also demonstrated efficacy in CKD models. Compound α-ketoacid tablets exhibit anti-fibrotic effects by inhibiting NF-κB and MAPK signaling, reducing apoptosis, and ameliorating IRI-induced injury. Similarly, high-dose oral vitamin B12 significantly attenuates DNA damage responses and caspase-3 expression, highlighting its potential as a safe and effective antifibrotic agent [ 117 ]. Withaferin A, a steroidal lactone known for pro-apoptotic properties, exerts renoprotective effects by suppressing endoplasmic reticulum (ER) stress-related apoptosis. It inhibits the CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) pathway and reverses the expression of key apoptotic markers, including glucose-regulated protein 78 (GRP78) and cleaved caspase-12 [ 118 ]. Collectively, these findings highlight apoptosis-related pathways as central mediators of CKD progression. With advances in molecular profiling and therapeutic screening, a growing number of small molecules are being identified as promising antifibrotic agents. We summarize these developments in Fig. 3 , offering a foundation for future translational research and innovative therapeutic strategies for renal fibrosis. Fig. 3. Open in a new tab Apoptosis mechanism and targeted small molecules in chronic kidney disease (CKD). Ruxolitinib, relaxin, and hydroxychloroquine target key signaling pathways involved in apoptosis regulation, including Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), and mothers against decapentaplegic homolog (Smad). By modulating these pathways, these compounds inhibit pro-apoptotic signals and promote cell survival, demonstrating therapeutic potential in CKD. c-Myc: cellular myelocytomatosis oncogene; Bcl-2: B-cell lymphoma 2; SIN: sinomenine; PRP: platelet-rich plasma; FADD: fas-associated protein with death domain; RIPK3: receptor-interacting serine/threonine-protein kinase 3; TNFR1: tumor necrosis factor (TNF) receptor superfamily member 1a; TRADD: TNF receptor-associated death domain protein; NEMO: nuclear factor-κB (NF-κB) essential modulator; TANK: TRAF family member-associated NF-κB activator; C-FLIP: cellular FLICE inhibitory protein; BID: Bcl-2 homology 3 domain (BH3)-interacting domain death agonist; tBID: truncated BH3 interacting domain death agonis; BAK: Bcl-2 antagonist/killer; BAX: Bcl-2-associated X protein; Cyt c: cytochrome c; APAF1: apoptotic protease-activating factor 1; MOMP: mitochondrial outer membrane permeabilization; SMAC: second mitochondria-derived activator of caspases; RTK: receptor tyrosine kinase; TSC1/2: tuberous sclerosis complex 1/2; Rheb: Ras homolog enriched in brain; mTORC1: mechanistic target of rapamycin complex 1; TGF-β: transforming growth factor-β. 4. Targeting autophagy-dependent cell death with small molecules in CKD Several synthetic drugs and natural compounds exhibit therapeutic potential in CKD by modulating autophagy through diverse mechanisms. Among synthetic agents, PA-S14, a novel liver kinase B1 (LKB1) activator, can stimulate LKB1 phosphorylation and promote the formation of the mouse protein-25 (MO25)/STE20-related adaptor (STRAD) complex, thereby activating the LKB1/adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. This activation enhances autophagosome maturation, improves autophagic flux, and restores mitochondrial homeostasis in RTECs, ultimately delaying renal fibrosis [ 119 ]. Conversely, the autophagy inhibitor 3-methyladenine (3-MA) alleviates uric acid-induced hyperuricemic nephropathy by mitigating autophagy-dependent cell death. Treatment with 3-MA preserves renal tissue structure, improves renal function, reduces autophagic vacuole formation, and lowers microalbuminuria. Additionally, 3-MA suppresses immune cell infiltration and reduces the expression of pro-fibrotic cytokines and chemokines in injured kidneys, highlighting its therapeutic utility in hyperuricemic nephropathy [ 120 ]. Rapamycin, a widely studied mTOR inhibitor, reduces renal fibrosis and ameliorates diabetic kidney injury by modulating autophagy-dependent cell death and preventing podocyte apoptosis. Its derivative, everolimus, exhibits enhanced renal selectivity and has demonstrated protective effects in CKD following lung transplantation [ 121 ]. Metformin, an FDA-approved first-line therapy for type 2 diabetes, exerts renoprotective effects in DN through activation of the AMPK/SIRT1/forkhead box protein O1 (FOXO1) axis. By enhancing autophagic activity, metformin mitigates glucose and lipid metabolic disturbances, oxidative stress, and inflammation, while also reducing hepatic gluconeogenesis and renal cellular injury [ 122 ]. Natural compounds also play a pivotal role in modulating autophagy in CKD. Resveratrol enhances mitophagy and activates the PI3K/Akt/heme oxygenase-1 (HO-1) and mTOR pathways to inhibit apoptosis, thereby improving intestinal barrier integrity disrupted by uremic toxins in CKD [ 123 ]. Pterostilbene, a natural resveratrol analogue, has been shown to induce autophagy-dependent cell death, inhibit NLRP3 inflammasome activation, and suppress epithelial-mesenchymal transition (EMT), thereby preventing renal fibrosis. Sulforaphane restores autophagic flux to protect against mitochondrial and lipid metabolism damage, significantly reducing kidney injury in UUO rat models [ 124 ]. Complanatoside A exerts anti-fibrotic effects in DN by targeting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and suppressing activating transcription factor 4 (ATF4)-driven autophagy [ 125 ]. Emerging natural agents such as calycosin promote autophagy via activation of the AMPK/S-phase kinase-associated protein 2 (Skp2)/coactivator-associated arginine methyltransferase 1 (CARM1) signaling cascade, while quercetin induces mitophagy through the SIRT1/PTEN-induced kinase 1 (PINK1)/Parkin pathway, thereby attenuating renal tubular cell senescence. Collectively, these compounds converge on critical autophagy-related signaling pathways, including AMPK, mTOR, and nuclear factor erythroid 2-related factor 2 (Nrf2), to alleviate oxidative stress, inflammation, and fibrosis in CKD. The therapeutic potential of additional small molecules targeting autophagy-dependent cell death in CKD is summarized in Fig. 4 . These findings highlight the importance of selective autophagy-dependent cell death modulation as a promising strategy for CKD intervention. Fig. 4. Open in a new tab Autophagy-dependent cell death mechanism and potential therapeutic targets in chronic kidney disease (CKD). (A) Canonical autophagy is initiated when stress signals activate mammalian target of rapamycin (mTOR), adenosine monophosphate (AMP)‑activated protein kinase (AMPK), phosphoinositide 3‑kinase (PI3K), and extracellular signal‑regulated kinase 1/2 (ERK1/2), leading to formation of the UNC‑51‑like kinases 1 and 2 (ULK1/2)-autophagy‑related protein 13 (ATG13) complex and recruitment of the ATG12-ATG5 complex to initiate phagophore formation. ATG4 processes microtubule‑associated protein 1 light chain 3 (LC3) to promote autophagosome expansion. (B) Non-canonical autophagy occurs independently of mTOR, involving ultraviolet (UV) radiation resistance‑associated gene (UVRAG) and beclin‑1, leading to phagosome formation and fusion with lysosomes to form LC3-associated phagosomes (LAPosomes) for degradation. Regulators such as B‑cell lymphoma 2 (Bcl‑2), p62/sequestosome 1 (SQSTM1), and autophagy-related fyve protein (ALFY) intersect with autophagy pathways. PAS: phagophore assembly site; FIP200: focal adhesion kinase (FAK) family interacting protein of 200 kDa; VPS34: vacuolar protein sorting-associated protein 34; MEK1/2: mitogen-activated protein kinase 1/2; Raf: rapidly accelerated fibrosarcoma; Ras: rat sarcoma; NBR1: NBR1 autophagy cargo receptor; LAMP2: lysosomal-associated membrane protein 2; RAB7A: ras-related protein Rab-7A; NOX2: nadph oxidase 2; PI3P: phosphatidylinositol 3-phosphate; ROS: reactive oxygen species. 5. Targeting regulated necrosis with small molecules in CKD 5.1. Small molecules targeting pyroptosis Caspase-1, the central executioner of pyroptosis, has emerged as a promising therapeutic target in CKD. Among caspase-1 inhibitors, VX-765 stands out due to its favorable pharmacokinetics, high bioavailability, and low toxicity. Clinical trials have confirmed its safety in humans with conditions such as psoriasis and epilepsy (Trial Nos.: NCT00205465 and NCT01048255 ). In DN mouse models, VX-765 significantly ameliorated renal dysfunction, tubular injury, and inflammation without affecting systemic parameters such as blood glucose or body weight [ 126 ]. Similarly, Z-YVAD-FMK, another selective caspase-1 inhibitor, has been shown to reduce caspase-1 and GSDMD expression, improve renal function in brain-dead rat models, and enhance the viability of NRK-52E renal epithelial cells. Beyond direct enzymatic inhibitors, canakinumab, a high-affinity monoclonal antibody targeting IL-1β, has shown efficacy in mitigating systemic inflammation and cardiovascular risk in clinical populations [ 127 ]. In patients with moderate CKD, canakinumab significantly reduced the incidence of myocardial infarction and was well-tolerated over five years across a wide dose range [ 128 ]. However, its direct renoprotective efficacy remains to be definitively demonstrated. Natural compounds also contribute significantly to the modulation of pyroptosis in CKD. Tanshinone IIA, a major active constituent of Salvia miltiorrhiza , inhibits the NLRP3/caspase-1/GSDMD signaling axis in RTECs, thereby suppressing pyroptosis and reducing ECM gene expression. It has also been found to human renal glomerular endothelial cells (HRGECs) by suppressing ROS-induced NLRP3 activation and IL-1β release, demonstrating efficacy comparable to valsartan [ 129 ]. Berberine, another bioactive natural compound, alleviates tubular epithelial pyroptosis by downregulating methyltransferase-like 3 (METTL3) and modulating the adapter apoptosis-associated speck-like protein containing a CARD (ASC)/caspase-1/GSDMD pathway [ 130 ]. Calycosin, a flavonoid compound, attenuates pyroptosis in streptozotocin-induced DN by targeting the NF-κB/NLRP3/thioredoxin interacting protein (TXNIP) axis. Notably, a dose of 10 mg/kg calycosin provided superior renoprotection compared to N -acetylcysteine (500 mg/kg), while 5 mg/kg did not yield significant effects [ 131 ]. Several FDA-approved drugs originally developed for other indications have shown potential for pyroptosis-targeted CKD therapy. Disulfiram, widely used for alcohol dependence and certain cancers, can act as a potent inhibitor of GSDMD pore formation by preventing caspase-11-mediated activation. While it cannot reverse existing GSDMD cleavage, disulfiram effectively prevents its activation and offers a cost-effective alternative to agents such as VX-765 and Z-YVAD-FMK. Importantly, future studies may explore the enhancement of disulfiram's efficacy through structural modification or combination therapy. In summary, caspase-1-mediated pyroptosis is a pivotal mechanism driving renal fibrosis and CKD progression. Targeted inhibition of this pathway using caspase-1 inhibitors (e.g., VX-765 and Z-YVAD-FMK), cytokine neutralization (e.g., canakinumab), natural agents (e.g., tanshinone IIA, berberine, and calycosin), and drug repurposing (e.g., disulfiram) offers promising avenues for therapy. Future research should prioritize clinical validation of these approaches and evaluate combinatorial regimens to optimize anti-fibrotic and nephroprotective outcomes. Additional candidate molecules targeting pyroptosis are summarized in Fig. 5 A. Fig. 5. Open in a new tab Regulated necrosis mechanisms and potential therapeutic targets in chronic kidney disease (CKD). (A) Pyroptosis: in CKD, pyroptosis is initiated when pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) activate inflammasomes such as nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 1 (NLRP1), NLRP3, and NOD-like receptor C4 (NLRC4) through Toll-like receptors (TLRs). This triggers caspase-1 to cleave pro-inflammatory cytokines pro-interleukin (IL)-1β and pro-IL-18, and gasdermin D (GSDMD), forming membrane pores that release cytokines. Therapeutic inhibitors include canakinumab and anakinra, which target IL-1β, as well as cucurbitacin B and berberine, which modulate inflammasome activity. (B) Ferroptosis: ferroptosis results from iron-dependent lipid peroxidation that damages kidney cells. Compounds like ferrostatin-1 and liproxstatin-1 (Lip-1) inhibit lipid peroxidation, while enzymes such as glutathione (GSH) peroxidase 4 (GPX4) and GSH reductase (GSR) maintain redox balance. In CKD, impaired antioxidant defenses exacerbate ferroptotic injury. (C) Necroptosis: necroptosis is mediated by activation of receptor interacting protein kinase-1 (RIPK1) and RIPK3, which phosphorylate mixed lineage kinase domain-like protein (MLKL), causing membrane rupture. Inhibitors such as AZD5423 target RIPK3 and MLKL to prevent cell death. Regulatory proteins including cylindromatosis (CYLD), A20, and cellular inhibitors of apoptosis proteins (cIAPs) modulate necroptotic signaling, representing potential therapeutic targets in CKD. HMGB1: high mobility group box 1; LDH: lactate dehydrogenase; NF-κB: nuclear factor-κB; ASC: apoptosis-associated speck-like protein containing a CARD; NETosis: neutrophil extracellular trap formation; SLC7A11: solute carrier family 7 member 11; DPEP1: dipeptidase 1; GSGG: gadolinium scandium gallium garnet; NADPH: nicotinamide adenine dinucleotide phosphate; LOX: lipoxygenase; PUFA-PE: polyunsaturated fatty acid phosphatidylethanolamine; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; Smad: mothers against decapentaplegic homolog; TNF-α: tumor necrosis factor-α; TNFR1: TNF receptor superfamily member 1a; TRADD: TNF receptor-associated death domain protein; TGF-β: transforming growth factor-β. 5.2. Small molecules targeting ferroptosis Recent advances have increasingly focused on small-molecule therapeutics targeting ferroptosis as a strategy to alleviate CKD. Among these, liproxstatin-1 (Lip-1) is a well-characterized ferroptosis inhibitor that has demonstrated significant efficacy in reducing renal fibrosis in UUO models. Lip-1 suppresses fibroblast activation and proliferation via modulation of the early growth response protein 1 (EGR-1)/TP53/SLC7A11 signaling axis and inhibits pro-fibrotic paracrine signaling from epithelial cells, thereby attenuating I/R-induced AKI [ 43 ]. However, its clinical application is hampered by poor aqueous solubility, necessitating solvents like dimethyl sulfoxide (DMSO) or polyethylene glycol. Structural modification of Lip-1 to improve solubility and bioavailability could significantly enhance its translational potential. XJB-5-131, an emerging iron chelator, protects against I/R-induced renal injury by upregulating GPX4 and downregulating ACSL4, both of which are central to ferroptosis regulation [ 132 ]. The FDA-approved iron chelator deferoxamine (DFO) has shown therapeutic potential in CKD by reducing tissue iron accumulation, mitigating inflammation and fibrosis, lowering proteinuria, and preserving glomerular and tubular architecture. Despite its efficacy, DFO's utility is constrained by off-target toxicity and the requirement for frequent intravenous infusions. To address these limitations, renal-targeted nanochelators such as diisopropyl fluorophosphate (DFP)-NP have been developed, which demonstrate improved renal bioavailability and therapeutic performance [ 133 ]. This nanotechnology-based strategy offers a promising avenue for enhancing the safety and efficacy of iron chelation therapy. Natural compounds represent another important class of ferroptosis-targeting therapeutics. Cur has demonstrated protective effects against ferroptosis and oxidative stress triggered by para-aminophenol, primarily through activation of the sequestosome 1 (p62)/Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 signaling pathway. It also downregulates the TLR4/NF-κB axis and induces HO-1, thereby reducing inflammation and oxidative damage in CKD models. However, Cur's clinical translation is hindered by its rapid metabolism, poor solubility, and limited bioavailability. To overcome these barriers, Cur nanocrystals (Cur-Ncs) have been developed, which markedly enhance solubility, systemic absorption, and in vivo stability. These nanoformulations improve DN by boosting intracellular GSH and GPX4 levels [ 134 ]. Other natural compounds, including quercetin, silibinin, naringenin, and vitexin, have exhibited significant renoprotective effects in UUO-induced kidney injury by exerting antioxidant activity and suppressing lipid peroxidation [ 135 ]. Additionally, alpha-lipoic acid has been shown to restore system Xc − function and enhance GPX4 activity, thereby protecting against oxidative stress-induced renal injury. A comprehensive summary of these and other ferroptosis-modulating agents is presented in Fig. 5 B. Collectively, these therapeutic agents confer robust protection against oxidative damage in CKD by targeting key regulators of ferroptosis, including iron chelation, inhibition of lipid peroxidation, and enhancement of antioxidant defenses. Future research should prioritize the clinical translation of these findings, with a particular emphasis on leveraging nanotechnology and other advanced delivery platforms to optimize pharmacokinetics, tissue targeting, and therapeutic efficacy in kidney disease management. 5.3. Small molecules targeting necroptosis Small-molecule therapies targeting necroptosis in CKD have predominantly focused on disrupting the RIPK1/RIPK3/MLKL signaling cascade. Among the earliest and most extensively studied compounds is necrostatin-1 (Nec-1), a selective RIPK1 kinase inhibitor. Nec-1 suppresses necroptotic cell death by inhibiting RIPK1 activity, thereby preventing the formation of necrotic bodies and attenuating renal I/R injury through modulation of the HIF-1α/miR-26a/transient receptor potential cation channel subfamily c member 6 (TRPC6)/PARP1 signaling axis [ 136 ]. However, its clinical translation has been hindered by a narrow structure-activity relationship (SAR) and limited metabolic stability [ 137 ]. In contrast, Cpd-71, a newer RIPK1 inhibitor, exhibits superior efficacy in models of cisplatin-induced nephrotoxicity. It inhibits RIPK1 phosphorylation more robustly, disrupts RIPK1–RIPK3 complex formation, and prevents MLKL phosphorylation and translocation, thereby offering more effective renal protection. As for RIPK3 inhibition, GSK872 is a well-established agent that blocks MLKL-mediated necroptosis. However, at high concentrations, GSK872 may paradoxically trigger apoptosis [ 138 ]. To address this limitation, a novel RIPK3 inhibitor, AZD5423, was developed through structure-based design and computational modeling. AZD5423 demonstrates enhanced binding affinity, superior suppression of necroptosis, and greater therapeutic efficacy in cisplatin- and I/R injury-induced AKI models, highlighting its potential as a next-generation clinical candidate [ 139 ]. Beyond direct necroptosis inhibitors, several repurposed drugs have shown nephroprotective effects via necroptosis modulation. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for type 2 diabetes, reduces renal fibrosis by modulating the Wnt3α/β-catenin/glycogen synthase kinase 3 (GSK-3) pathway and suppressing RIPK1/RIPK3/MLKL signaling-mediated necroptosis. Natural compounds are also emerging as promising necroptosis modulators. Paeoniflorin, the principal active ingredient of Paeonia lactiflora , can promote degradation of TNFR1 in podocytes, thereby disrupting RIPK1/RIPK3 interactions and attenuating diabetic podocyte injury, with efficacy comparable to Nec-1. Similarly, apigenin mitigates lipopolysaccharide (LPS)-induced necroptosis by enhancing endosomal sorting complexes for transport-III (ESCRT-III)-dependent plasma membrane repair and promoting mitophagy, contributing to renal cell survival [ 140 ]. A novel therapeutic avenue is represented by inaxaplin, a selective inhibitor of APOL1 channel activity. Inaxaplin protects renal cells from necroptosis in vitro and in preclinical models. In a phase 2A clinical trial (Trial No.: NCT04340362 ) involving 16 participants (13 compliant), inaxaplin reduced the urine protein-to-creatinine ratio by 47.6% at week 13, suggesting its potential in treating proteinuric nephropathy in patients with two apolipoprotein L1 (APOL1) risk variants [ 141 ]. As summarized in Fig. 5 C, additional small molecules are being actively investigated for their anti-necroptotic properties in CKD. While most remain in the preclinical development phase, these findings collectively highlight necroptosis as a critical driver of renal pathology and underscore the need for continued clinical evaluation to validate safety, efficacy, and long-term benefits in human CKD. 6. Small molecules targeting two or more RCD subroutines against CKD Several small-molecule compounds have demonstrated renoprotective effects by concurrently targeting multiple forms of RCD. This multi-targeted approach offers synergistic benefits by attenuating cell loss, inflammation, and fibrosis, thereby slowing CKD progression. Rapamycin, an mTOR inhibitor, exemplifies this strategy by simultaneously inducing autophagy and suppressing both apoptosis and pyroptosis. In DN, rapamycin lowers the BAX/Bcl-2 ratio, reducing tubular cell apoptosis, and inhibits mTOR-mediated NF-κB activation, thereby suppressing NLRP3 inflammasome-driven pyroptosis and mitigating renal fibrosis [ 142 ]. Nec-1, a RIPK1 inhibitor, not only blocks necroptosis but also prevents apoptosis by inhibiting caspase-8. In I/R-induced AKI, Nec-1 reduces both RIPK1/RIPK3/MLKL-mediated necroptosis and caspase-3-dependent apoptosis, preserving renal structure and function [ 143 ]. Ferrostatin-1, primarily a ferroptosis inhibitor, also inhibits pyroptosis by scavenging lipid peroxides that activate the NLRP3 inflammasome. In CKD models, ferrostatin-1 preserves GPX4 activity, prevents GSDMD cleavage, and mitigates inflammation in proximal tubular cells [ 144 ]. Imperatorin, a plant-derived furanocoumarin, reduces oxidative stress, inflammation, and cell death by downregulating key ferroptosis markers including GPX4, SLC7A11, and TFR-1, while also diminishing renal cell apoptosis [ 145 ]. Beyond tubular injury, vascular calcification (VC), a hallmark of CKD, is also influenced by RCD. Irisin, a skeletal muscle-derived myokine, protects against VC by promoting autophagy, reducing ROS production, and suppressing NLRP3-mediated pyroptosis in vascular smooth muscle cells [ 146 ]. Magnoflorine, a natural alkaloid, attenuates CKD progression in high-fat/high-fructose-fed mice by enhancing Parkin/PINK1-mediated mitophagy, thereby suppressing NLRP3 activation and pyroptosis [ 147 ]. Similarly, isovitexin (IV), a bioactive flavonoid, improves renal outcomes in LPS-induced models by reducing glomerular atrophy, pyroptotic cytokine release, and promoting protective autophagy. MitoQ, a mitochondria-targeted antioxidant, has been shown to upregulate Nrf2 activity and restore PINK1-mediated mitophagy, thereby mitigating hyperglycemia-induced apoptosis and tubular damage in DN [ 148 ]. Resveratrol, a non-flavonoid polyphenol, effectively attenuated high-glucose-induced apoptosis in both podocytes and diabetic mouse models through autophagy activation mediated by miR-383–5p suppression. Lastly, kaempferitrin, a flavonoid isolated from Bauhinia forficata , significantly ameliorates renal injury in UUO models. It reduces tubular necrosis, fibrosis, and inflammation, and blocks NOX4-mediated ferroptosis in tubular cells [ 149 ]. Collectively, these multi-targeted agents provide robust renoprotection by modulating interconnected RCD pathways. Their ability to concurrently inhibit multiple cell death mechanisms offers a novel therapeutic paradigm for treating CKD. Future research should focus on optimizing their pharmacokinetics, exploring synergistic combinations, and validating efficacy in clinical settings. 7. Conclusion and perspectives Targeting RCD pathways with small molecules is emerging as a promising therapeutic strategy for CKD, offering an avenue to address its complex and multifactorial pathogenesis. However, realizing this potential depends on the development of delivery systems that improve both renal specificity and bioavailability. Recent innovations, such as nanocarriers, hydrophobic compounds like quercetin, ligand-mediated targeting, and stimuli-responsive platforms, have enhanced the precision of drug delivery to kidney tissues. Innovations in kidney-targeted approaches, particularly those involving biomimetic and micro/nano-engineered technologies, are expanding these capabilities. For example, NPs coated with RTEC membranes have demonstrated improved targeting efficiency, as evidenced by enhanced delivery of the stimulator of IFN genes (STING) inhibitor C176. Looking ahead, combining delivery strategies to modulate multiple RCD pathways could more effectively address overlapping processes such as cell death, inflammation, and fibrosis. Artificial intelligence (AI) further offers a powerful tool to optimize dosing strategies and improve therapeutic precision. In parallel with these technological developments, biomarker discovery is advancing the field of precision medicine in CKD. A recent metabolomic analysis of 1761 patients identified 26 metabolites associated with symptoms (e.g., fatigue and anorexia) and clinical outcomes (e.g., renal failure and mortality). Notably, tryptophan derivatives were linked to nausea, and indoxyl sulfate was identified as a predictor of cardiovascular risk. Elevated levels of uremic toxins were associated with reduced estimated glomerular filtration rate (eGFR) and higher mortality, reinforcing their value as both mechanistic and prognostic biomarkers. These findings complement traditional markers like eGFR and proteinuria and are further supported by emerging imaging technologies such as fibrosis-targeted MRI, which enable more accurate risk assessment and monitoring. Clinical evaluation of RCD-targeted small molecules should prioritize large-scale, adaptive, and stratified trial designs that can assess efficacy across diverse CKD subtypes and track long-term safety, particularly for systemically active agents like iron chelators and inflammasome inhibitors. Strong pharmacovigilance will be essential to identify and mitigate risks such as drug interactions, tissue-specific toxicity, and unintended effects on cell death pathways. Additional challenges remain. These include scaling up complex delivery systems, ensuring adherence to long-term treatment, and evaluating the cost-effectiveness of novel therapies to promote equitable access. Promising approaches, such as NP-based delivery, CTPs, and CPPs, offer the potential to direct therapies to specific kidney cell populations, maximizing efficacy while minimizing systemic toxicity. In conclusion, small molecules that modulate RCD pathways represent a transformative approach to CKD treatment. Integrating targeted delivery platforms, AI-driven regimen optimization, and biomarker-informed precision medicine could slow disease progression and substantially improve patient outcomes. Achieving this goal will require coordinated efforts across pharmacology, bioengineering, and clinical research to bring these innovations into clinical practice. CRediT authorship contribution statement Wen-Kai Yu: Writing – original draft, Investigation, Conceptualization. Qing-Ru Zhu: Writing – original draft, Investigation, Conceptualization. Li Zhou: Validation, Supervision, Resources. Xin-Lei Shen: Validation, Supervision, Resources. Tian-Yang Cheng: Validation, Supervision, Resources. Yi-Ni Bao: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Gang Cao: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments This work was financially supported by the National Natural Science Foundation of China (Grant No.: 82204625), the Natural Science Foundation of Zhejiang Province, China (Grant No.: LQ23H280013), the Chinese Medicine Research Program of Zhejiang Province, China (Grant Nos.: 2021ZZ009 and 2023ZR009), and the Graduate Research Fund Project of Zhejiang Chinese Medical University, China (Grant No.: 2023YKJ02). We appreciate the great help from the Pharmaceutical Research Center and Medical Research Center, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University (Hangzhou, China). All figures, including Graphical abstract, were drawn by using BioRender.com . Footnotes Peer review under responsibility of Xi'an Jiaotong University. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.jpha.2025.101427 . Contributor Information Yi-Ni Bao, Email: [email protected]. Gang Cao, Email: [email protected]. Appendix A. Supplementary data The following are the Supplementary data to this article. Multimedia component 1 mmc1.pdf (179.5KB, pdf) Multimedia component 2 mmc2.pdf (298.8KB, pdf) Multimedia component 3 mmc3.pdf (429.4KB, pdf) Multimedia component 4 mmc4.pdf (323KB, pdf) Multimedia component 5 mmc5.pdf (444KB, pdf) Multimedia component 6 mmc6.pdf (316.8KB, pdf) References 1. Foreman K.J., Marquez N., Dolgert A., et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet. 2018;392:2052–2090. doi: 10.1016/S0140-6736(18)31694-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Anders H.J., Huber T.B., Isermann B., et al. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat. Rev. Nephrol. 2018;14:361–377. doi: 10.1038/s41581-018-0001-y. [ DOI ] [ PubMed ] [ Google Scholar ] 3. Borges J.P., Sætra R., Volchuk A., et al. Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death. eLife. 2022;11 doi: 10.7554/eLife.78609. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 4. Galluzzi L., Vitale I., Aaronson S.A., et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25:486–541. doi: 10.1038/s41418-017-0012-4. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Webster A.C., Nagler E.V., Morton R.L., et al. Chronic kidney disease. Lancet. 2017;389:1238–1252. doi: 10.1016/S0140-6736(16)32064-5. [ DOI ] [ PubMed ] [ Google Scholar ] 6. Chen J., Li H., Bai Y., et al. Spatially resolved multi-omics unravels region-specific responses, microenvironment remodeling and metabolic reprogramming in aristolochic acid nephropathy. Inn. Med. 2024;2 [ Google Scholar ] 7. Sanz A.B., Sanchez-Niño M.D., Ramos A.M., et al. Regulated cell death pathways in kidney disease. Nat. Rev. Nephrol. 2023;19:281–299. doi: 10.1038/s41581-023-00694-0. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 8. Xie T., Yao L., Li X. Advance in iron metabolism, oxidative stress and cellular dysfunction in experimental and human kidney diseases. Antioxidants. 2024;13:659. doi: 10.3390/antiox13060659. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 9. Ai Y., Meng Y., Yan B., et al. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol. Cell. 2024;84:170–179. doi: 10.1016/j.molcel.2023.11.040. [ DOI ] [ PubMed ] [ Google Scholar ] 10. Belavgeni A., Meyer C., Stumpf J., et al. Ferroptosis and necroptosis in the kidney. Cell Chem. Biol. 2020;27:448–462. doi: 10.1016/j.chembiol.2020.03.016. [ DOI ] [ PubMed ] [ Google Scholar ] 11. Mishima E., Nakamura T., Doll S., et al. Recommendations for robust and reproducible research on ferroptosis. Nat. Rev. Mol. Cell Biol. 2025;26:615–630. doi: 10.1038/s41580-025-00843-2. [ DOI ] [ PubMed ] [ Google Scholar ] 12. Tajaldini M., Poorkhani A., Amiriani T., et al. Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance. Eur. J. Pharmacol. 2023;957 doi: 10.1016/j.ejphar.2023.175991. [ DOI ] [ PubMed ] [ Google Scholar ] 13. Dhillon S. Daprodustat: first approval. Drugs. 2020;80:1491–1497. doi: 10.1007/s40265-020-01384-y. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 14. Hu X., Zhao W., Deng J., et al. Mangiferin alleviates renal inflammatory injury in spontaneously hypertensive rats by inhibiting MCP-1/CCR2 signaling pathway. Chin. Herb. Med. 2023;15:556–563. doi: 10.1016/j.chmed.2022.12.008. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 15. Flores J., Noël A., Foveau B., et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat. Commun. 2018;9:3916. doi: 10.1038/s41467-018-06449-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 16. Xin W., Gong S., Chen Y., et al. Self-assembling P38 peptide inhibitor nanoparticles ameliorate the transition from acute to chronic kidney disease by suppressing ferroptosis. Adv. Healthc. Mater. 2024;13 doi: 10.1002/adhm.202400441. [ DOI ] [ PubMed ] [ Google Scholar ] 17. Yang X., Thorngren D., Chen Q., et al. Protective role of relaxin in a mouse model of aristolochic acid nephropathy. Biomed. Pharmacother. 2019;115 doi: 10.1016/j.biopha.2019.108917. [ DOI ] [ PubMed ] [ Google Scholar ] 18. Bai Y., Wang W., Yin P., et al. Ruxolitinib alleviates renal interstitial fibrosis in UUO mice. Int. J. Biol. Sci. 2020;16:194–203. doi: 10.7150/ijbs.39024. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 19. Sun L., Yang Z., Zhang J., et al. Isoliquiritigenin attenuates acute renal injury through suppressing oxidative stress, fibrosis and JAK2/STAT3 pathway in streptozotocin-induced diabetic rats. Bioengineered. 2021;12:11188–11200. doi: 10.1080/21655979.2021.2006978. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 20. Zhu M., Wang H., Chen J., et al. Sinomenine improve diabetic nephropathy by inhibiting fibrosis and regulating the JAK2/STAT3/SOCS1 pathway in streptozotocin-induced diabetic rats. Life Sci. 2021;265 doi: 10.1016/j.lfs.2020.118855. [ DOI ] [ PubMed ] [ Google Scholar ] 21. Li D., Yu K., Feng F., et al. Hydroxychloroquine alleviates renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway. Biochem. Biophys. Res. Commun. 2022;610:154–161. doi: 10.1016/j.bbrc.2022.04.058. [ DOI ] [ PubMed ] [ Google Scholar ] 22. Zhou S., He Y., Zhang W., et al. Ophiocordyceps lanpingensis polysaccharides alleviate chronic kidney disease through MAPK/NF-κB pathway. J. Ethnopharmacol. 2021;276 doi: 10.1016/j.jep.2021.114189. [ DOI ] [ PubMed ] [ Google Scholar ] 23. Shi J., Li S., Yi L., et al. Levistolide a attenuates acute kidney injury in mice by inhibiting the TLR-4/NF-κB pathway. Drug Des. Dev. Ther. 2024;18:5583–5597. doi: 10.2147/DDDT.S476548. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 24. Keshk W.A., Zahran S.M. Mechanistic role of cAMP and hepatocyte growth factor signaling in thioacetamide-induced nephrotoxicity: unraveling the role of platelet rich plasma. Biomed. Pharmacother. 2019;109:1078–1084. doi: 10.1016/j.biopha.2018.10.121. [ DOI ] [ PubMed ] [ Google Scholar ] 25. Mahmoud N.M., Elshazly S.M., Rezq S. Geraniol protects against cyclosporine A-induced renal injury in rats: role of Wnt/β-catenin and PPARγ signaling pathways. Life Sci. 2022;291 doi: 10.1016/j.lfs.2021.120259. [ DOI ] [ PubMed ] [ Google Scholar ] 26. Afrin M.R., Arumugam S., Rahman M.A., et al. Curcumin reduces the risk of chronic kidney damage in mice with nonalcoholic steatohepatitis by modulating endoplasmic reticulum stress and MAPK signaling. Int. Immunopharmacol. 2017;49:161–167. doi: 10.1016/j.intimp.2017.05.035. [ DOI ] [ PubMed ] [ Google Scholar ] 27. Guo L., Tan K., Luo Q., et al. Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy. Biomol. Biomed. 2020;20:372–380. doi: 10.17305/bjbms.2019.4410. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 28. Liu X., Chen J., Sun N., et al. Ginsenoside Rb1 ameliorates autophagy via the AMPK/mTOR pathway in renal tubular epithelial cells in vitro and in vivo. Int. J. Biol. Macromol. 2020;163:996–1009. doi: 10.1016/j.ijbiomac.2020.07.060. [ DOI ] [ PubMed ] [ Google Scholar ] 29. Tu Y., Gu L., Chen D., et al. Rhein inhibits autophagy in rat renal tubular cells by regulation of AMPK/mTOR signaling. Sci. Rep. 2017;7 doi: 10.1038/srep43790. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 30. Dusabimana T., Park E.J., Je J., et al. Geniposide improves diabetic nephropathy by enhancing ULK1-mediated autophagy and reducing oxidative stress through AMPK activation. Int. J. Mol. Sci. 2021;22:1651. doi: 10.3390/ijms22041651. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 31. Tao M., Zheng D., Liang X., et al. Tripterygium glycoside suppresses epithelial-to-mesenchymal transition of diabetic kidney disease podocytes by targeting autophagy through the mTOR/Twist1 pathway. Mol. Med. Rep. 2021;24:592. doi: 10.3892/mmr.2021.12231. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Retracted ] 32. Li X., Wang S., Han Z., et al. Triptolide restores autophagy to alleviate diabetic renal fibrosis through the miR-141-3p/PTEN/Akt/mTOR pathway. Mol. Ther. Nucleic Acids. 2024;35 doi: 10.1016/j.omtn.2024.102343. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 33. Yang F., Zhang Y., Dong L., et al. Cordyceps cicadae ameliorates inflammatory responses, oxidative stress, and fibrosis by targeting the PI3K/mTOR-mediated autophagy pathway in the renal of MRL/lpr mice, Immun. Inflamm. Dis. 2024;12 doi: 10.1002/iid3.1168. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 34. Han Y., Tang S., Liu Y., et al. AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice. Cell Death Dis. 2021;12:925. doi: 10.1038/s41419-021-04184-8. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 35. Ling Y.H., Krishnan S.M., Chan C.T., et al. Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. Pharmacol. Res. 2017;116:77–86. doi: 10.1016/j.phrs.2016.12.015. [ DOI ] [ PubMed ] [ Google Scholar ] 36. Masola V., Carraro A., Granata S., et al. In Vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells. J. Transl. Med. 2019;17:12. doi: 10.1186/s12967-019-1770-1. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 37. Kim K.H., Lee I.S., Park J.Y., et al. Cucurbitacin B induces hypoglycemic effect in diabetic mice by regulation of AMP-activated protein kinase alpha and glucagon-like peptide-1 via bitter taste receptor signaling. Front. Pharmacol. 2018;9:1071. doi: 10.3389/fphar.2018.01071. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 38. Wu M., Yang Z., Zhang C., et al. Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. Metabolism. 2021;118 doi: 10.1016/j.metabol.2021.154748. [ DOI ] [ PubMed ] [ Google Scholar ] 39. Yang Z., He Y., Ma Q., et al. Alleviative effect of melatonin against the nephrotoxicity induced by cadmium exposure through regulating renal oxidative stress, inflammatory reaction, and fibrosis in a mouse model. Ecotoxicol. Environ. Saf. 2023;265 doi: 10.1016/j.ecoenv.2023.115536. [ DOI ] [ PubMed ] [ Google Scholar ] 40. Ma Z., Zhu L., Wang S., et al. Berberine protects diabetic nephropathy by suppressing epithelial-to-mesenchymal transition involving the inactivation of the NLRP3 inflammasome. Ren. Fail. 2022;44:923–932. doi: 10.1080/0886022X.2022.2079525. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 41. El Karoui K., Viau A., Dellis O., et al. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat. Commun. 2016;7 doi: 10.1038/ncomms10330. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 42. Chen J., Ou Z., Gao T., et al. Ginkgolide B alleviates oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination to improve diabetic nephropathy. Biomed. Pharmacother. 2022;156 doi: 10.1016/j.biopha.2022.113953. [ DOI ] [ PubMed ] [ Google Scholar ] 43. Zhang B., Chen X., Ru F., et al. Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis. Cell Death Dis. 2021;12:843. doi: 10.1038/s41419-021-04137-1. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 44. Wang B., Yang L., Yang L., et al. Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis. Acta Pharmacol. Sin. 2024;45:150–165. doi: 10.1038/s41401-023-01156-w. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 45. Qiu C., Chen B., Zhu H., et al. Gastrodin alleviates cisplatin nephrotoxicity by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway. J. Ethnopharmacol. 2024;319 doi: 10.1016/j.jep.2023.117282. [ DOI ] [ PubMed ] [ Google Scholar ] 46. Yang S., Pei T., Wang L., et al. Salidroside alleviates renal fibrosis in SAMP8 mice by inhibiting ferroptosis. Molecules. 2022;27:8039. doi: 10.3390/molecules27228039. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 47. Lo Y.H., Yang S., Cheng C.C., et al. Nobiletin alleviates ferroptosis-associated renal injury, inflammation, and fibrosis in a unilateral ureteral obstruction mouse model. Biomedicines. 2022;10:595. doi: 10.3390/biomedicines10030595. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 48. Hou B., Ma P., Yang X., et al. In silico prediction and experimental validation to reveal the protective mechanism of puerarin against excessive extracellular matrix accumulation through inhibiting ferroptosis in diabetic nephropathy. J. Ethnopharmacol. 2024;319 doi: 10.1016/j.jep.2023.117281. [ DOI ] [ PubMed ] [ Google Scholar ] 49. Yang L., Guo J., Yu N., et al. Tocilizumab mimotope alleviates kidney injury and fibrosis by inhibiting IL-6 signaling and ferroptosis in UUO model. Life Sci. 2020;261 doi: 10.1016/j.lfs.2020.118487. [ DOI ] [ PubMed ] [ Google Scholar ] 50. Ye Y., Chen A., Li L., et al. Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification. Kidney Int. 2022;102:1259–1275. doi: 10.1016/j.kint.2022.07.034. [ DOI ] [ PubMed ] [ Google Scholar ] 51. Li C., Xie N., Li Y., et al. N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation. Free Radic. Biol. Med. 2019;130:512–527. doi: 10.1016/j.freeradbiomed.2018.11.006. [ DOI ] [ PubMed ] [ Google Scholar ] 52. Song J., Wang H., Sheng J., et al. Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation. Mol. Med. 2023;29:147. doi: 10.1186/s10020-023-00735-1. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 53. Linkermann A., Skouta R., Himmerkus N., et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl. Acad. Sci. USA. 2014;111:16836–16841. doi: 10.1073/pnas.1415518111. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 54. Chen X., Zhuang C., Ren Y., et al. Identification of the raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3. Br. J. Pharmacol. 2019;176:2095–2108. doi: 10.1111/bph.14653. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 55. Prajapati S., Tomar B., Srivastava A., et al. 6, 7-Dihydroxycoumarin ameliorates crystal-induced necroptosis during crystal nephropathies by inhibiting MLKL phosphorylation. Life Sci. 2021;271 doi: 10.1016/j.lfs.2021.119193. [ DOI ] [ PubMed ] [ Google Scholar ] 56. Rui C., Shi S., Ren W., et al. The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis. Biochem. Pharmacol. 2021;188 doi: 10.1016/j.bcp.2021.114542. [ DOI ] [ PubMed ] [ Google Scholar ] 57. Liu W., Chen B., Wang Y., et al. RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism. Proc. Natl. Acad. Sci. USA. 2018;115:1475–1484. doi: 10.1073/pnas.1716959115. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 58. Maremonti F., Meyer C., Linkermann A. Mechanisms and models of kidney tubular necrosis and nephron loss. J. Am. Soc. Nephrol. 2022;33:472–486. doi: 10.1681/ASN.2021101293. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 59. Lazebnik Y.A., Kaufmann S.H., Desnoyers S., et al. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994;371:346–347. doi: 10.1038/371346a0. [ DOI ] [ PubMed ] [ Google Scholar ] 60. Moujalled D., Southon A.G., Saleh E., et al. BH3 mimetic drugs cooperate with temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells. Cell Death Differ. 2022;29:1335–1348. doi: 10.1038/s41418-022-00977-2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 61. Bao Y., Yang Q., Shen X., et al. Targeting tumor suppressor p53 for organ fibrosis therapy. Cell Death Dis. 2024;15:336. doi: 10.1038/s41419-024-06702-w. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 62. Cheng E.H.Y., Sheiko T.V., Fisher J.K., et al. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science. 2003;301:513–517. doi: 10.1126/science.1083995. [ DOI ] [ PubMed ] [ Google Scholar ] 63. Yang X., Okamura D.M., Lu X., et al. CD36 in chronic kidney disease: novel insights and therapeutic opportunities. Nat. Rev. Nephrol. 2017;13:769–781. doi: 10.1038/nrneph.2017.126. [ DOI ] [ PubMed ] [ Google Scholar ] 64. Kuppe C., Ibrahim M.M., Kranz J., et al. Decoding myofibroblast origins in human kidney fibrosis. Nature. 2021;589:281–286. doi: 10.1038/s41586-020-2941-1. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 65. Chen X., Gu L., Cheng X., et al. miR-17-5p downregulation alleviates apoptosis and fibrosis in high glucose-induced human mesangial cells through inactivation of Wnt/β-catenin signaling by targeting KIF23. Environ. Toxicol. 2021;36:1702–1712. doi: 10.1002/tox.23280. [ DOI ] [ PubMed ] [ Google Scholar ] 66. Ma T., Li H., Liu H., et al. Neat1 promotes acute kidney injury to chronic kidney disease by facilitating tubular epithelial cells apoptosis via sequestering miR-129-5p. Mol. Ther. 2022;30:3313–3332. doi: 10.1016/j.ymthe.2022.05.019. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 67. Hu S., Han R., Shi J., et al. The long noncoding RNA LOC105374325 causes podocyte injury in individuals with focal segmental glomerulosclerosis. J. Biol. Chem. 2018;293:20227–20239. doi: 10.1074/jbc.RA118.005579. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 68. Tang B., Li W., Ji T., et al. Circ-AKT3 inhibits the accumulation of extracellular matrix of mesangial cells in diabetic nephropathy via modulating miR-296-3p/E-cadherin signals. J. Cell Mol. Med. 2020;24:8779–8788. doi: 10.1111/jcmm.15513. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 69. Codogno P., Mehrpour M., Proikas-Cezanne T. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat. Rev. Mol. Cell Biol. 2012;13:7–12. doi: 10.1038/nrm3249. [ DOI ] [ PubMed ] [ Google Scholar ] 70. Kroemer G., Levine B. Autophagic cell death: the story of a misnomer. Nat. Rev. Mol. Cell Biol. 2008;9:1004–1010. doi: 10.1038/nrm2527. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 71. Bialik S., Dasari S.K., Kimchi A. Autophagy-dependent cell death–where, how and why a cell eats itself to death. J. Cell Sci. 2018;131 doi: 10.1242/jcs.215152. jcs215152. [ DOI ] [ PubMed ] [ Google Scholar ] 72. Livingston M.J., Ding H., Huang S., et al. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy. 2016;12:976–998. doi: 10.1080/15548627.2016.1166317. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 73. Lenoir O., Jasiek M., Hénique C., et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy. 2015;11:1130–1145. doi: 10.1080/15548627.2015.1049799. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 74. Shang S., Li X., Wang H., et al. Targeted therapy of kidney disease with nanoparticle drug delivery materials. Bioact. Mater. 2024;37:206–221. doi: 10.1016/j.bioactmat.2024.03.014. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 75. Ding Y., Kim S.L., Lee S.Y., et al. Autophagy regulates TGF-β expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J. Am. Soc. Nephrol. 2014;25:2835–2846. doi: 10.1681/ASN.2013101068. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 76. Li J., Xiong M., Fu X., et al. Determining a multimodal aging clock in a cohort of Chinese women. Med. 2023;4:825–848.e13. doi: 10.1016/j.medj.2023.06.010. [ DOI ] [ PubMed ] [ Google Scholar ] 77. Jiang M., Wu S., Xie K., et al. The significance of ferroptosis in renal diseases and its therapeutic potential. Heliyon. 2024;10 doi: 10.1016/j.heliyon.2024.e35882. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 78. Zhou X., Zhao R., Lv M., et al. ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression. Brain Behav. Immun. 2023;109:331–343. doi: 10.1016/j.bbi.2023.02.012. [ DOI ] [ PubMed ] [ Google Scholar ] 79. Gupta A., Chakole S., Agrawal S., et al. Emerging insights into necroptosis: implications for renal health and diseases. Cureus. 2023;15 doi: 10.7759/cureus.43609. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 80. Elias E.E., Lyons B., Muruve D.A. Gasdermins and pyroptosis in the kidney. Nat. Rev. Nephrol. 2023;19:337–350. doi: 10.1038/s41581-022-00662-0. [ DOI ] [ PubMed ] [ Google Scholar ] 81. Amador-Martínez I., Aparicio-Trejo O.E., Bernabe-Yepes B., et al. Mitochondrial impairment: a link for inflammatory responses activation in the cardiorenal syndrome type 4. Int. J. Mol. Sci. 2023;24 doi: 10.3390/ijms242115875. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 82. Mueller A., Zhao Y., Cicek H., et al. Transcriptional and clonal characterization of cytotoxic T cells in crescentic glomerulonephritis. J. Am. Soc. Nephrol. 2023;34:1003–1018. doi: 10.1681/ASN.0000000000000116. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 83. Cheng Q., Pan J., Zhou Z., et al. Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy. Acta Pharmacol. Sin. 2021;42:954–963. doi: 10.1038/s41401-020-00525-z. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 84. Wang Y., Jiao B., Hu Z., et al. Critical role of histone deacetylase 3 in the regulation of kidney inflammation and fibrosis. Kidney Int. 2024;105:775–790. doi: 10.1016/j.kint.2024.01.010. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 85. Dixon S.J., Lemberg K.M., Lamprecht M.R., et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–1072. doi: 10.1016/j.cell.2012.03.042. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 86. Stockwell B.R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185:2401–2421. doi: 10.1016/j.cell.2022.06.003. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 87. Friedmann Angeli J.P., Schneider M., Proneth B., et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 2014;16:1180–1191. doi: 10.1038/ncb3064. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 88. Gao L., Zhang J., Yang T., et al. STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease. Mol. Ther. 2023;31:3084–3103. doi: 10.1016/j.ymthe.2023.07.026. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 89. Dai Y., Chen Y., Mo D., et al. Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease, commun. Biol. 2023;6:907. doi: 10.1038/s42003-023-05272-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 90. Bersuker K., Hendricks J.M., Li Z., et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–692. doi: 10.1038/s41586-019-1705-2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 91. Ru Q., Li Y., Chen L., et al. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct. Targeted Ther. 2024;9:271. doi: 10.1038/s41392-024-01969-z. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 92. Galluzzi L., Kepp O., Chan F.K., et al. Necroptosis: mechanisms and relevance to disease. Annu. Rev. Pathol. 2017;12:103–130. doi: 10.1146/annurev-pathol-052016-100247. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 93. Grootjans S., Vanden Berghe T., Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 2017;24:1184–1195. doi: 10.1038/cdd.2017.65. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 94. Newton K., Wickliffe K.E., Dugger D.L., et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574:428–431. doi: 10.1038/s41586-019-1548-x. [ DOI ] [ PubMed ] [ Google Scholar ] 95. Sureshbabu A., Patino E., Ma K.C., et al. RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction. JCI Insight. 2018;3 doi: 10.1172/jci.insight.98411. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 96. Srivastava A., Tomar B., Sharma P., et al. RIPK3-MLKL signaling activates mitochondrial CaMKII and drives intrarenal extracellular matrix production during CKD. Matrix Biol. 2022;112:72–89. doi: 10.1016/j.matbio.2022.08.005. [ DOI ] [ PubMed ] [ Google Scholar ] 97. Wang Y., Yu L., Li Y., et al. Supplemented Gegen Qinlian Decoction Formula attenuates podocyte mitochondrial fission and renal fibrosis in diabetic kidney disease by inhibiting TNF-α-mediated necroptosis, compared with empagliflozin. J. Ethnopharmacol. 2024;334 doi: 10.1016/j.jep.2024.118572. [ DOI ] [ PubMed ] [ Google Scholar ] 98. Lin Z., Chen A., Cui H., et al. Renal tubular epithelial cell necroptosis promotes tubulointerstitial fibrosis in patients with chronic kidney disease. FASEB J. 2022;36 doi: 10.1096/fj.202200706RR. [ DOI ] [ PubMed ] [ Google Scholar ] 99. Pandian N., Kanneganti T.D. PANoptosis: a unique innate immune inflammatory cell death modality. J. Immunol. 2022;209:1625–1633. doi: 10.4049/jimmunol.2200508. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 100. Singh A.B., Kaushal V., Megyesi J.K., et al. Cloning and expression of rat caspase-6 and its localization in renal ischemia/reperfusion injury. Kidney Int. 2002;62:106–115. doi: 10.1046/j.1523-1755.2002.00427.x. [ DOI ] [ PubMed ] [ Google Scholar ] 101. Ortiz A., Justo P., Sanz A., et al. Targeting apoptosis in acute tubular injury. Biochem. Pharmacol. 2003;66:1589–1594. doi: 10.1016/s0006-2952(03)00515-x. [ DOI ] [ PubMed ] [ Google Scholar ] 102. Müller T., Dewitz C., Schmitz J., et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell. Mol. Life Sci. 2017;74:3631–3645. doi: 10.1007/s00018-017-2547-4. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 103. Martin-Sanchez D., Fontecha-Barriuso M., Carrasco S., et al. TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proc. Natl. Acad. Sci. USA. 2018;115:4182–4187. doi: 10.1073/pnas.1716578115. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 104. Aubrey B.J., Kelly G.L., Janic A., et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018;25:104–113. doi: 10.1038/cdd.2017.169. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 105. Liu Y., Stockwell B.R., Jiang X., et al. p53-regulated non-apoptotic cell death pathways and their relevance in cancer and other diseases. Nat. Rev. Mol. Cell Biol. 2025;26:600–614. doi: 10.1038/s41580-025-00842-3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 106. Kang R., Zeh H.J., Lotze M.T., et al. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18:571–580. doi: 10.1038/cdd.2010.191. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 107. Kim D.H., Park J.S., Choi H.I., et al. The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD. Cell Death Dis. 2021;12:320. doi: 10.1038/s41419-021-03620-z. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 108. Radogna F., Dicato M., Diederich M. Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem. Pharmacol. 2015;94:1–11. doi: 10.1016/j.bcp.2014.12.018. [ DOI ] [ PubMed ] [ Google Scholar ] 109. Xie Y., Kang R., Klionsky D.J., et al. GPX4 in cell death, autophagy, and disease. Autophagy. 2023;19:2621–2638. doi: 10.1080/15548627.2023.2218764. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 110. Bertheloot D., Latz E., Franklin B.S. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell. Mol. Immunol. 2021;18:1106–1121. doi: 10.1038/s41423-020-00630-3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 111. Wu M., Jin Q., Xu X., et al. TP53RK drives the progression of chronic kidney disease by phosphorylating Birc5. Adv. Sci. 2023;10 doi: 10.1002/advs.202301753. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 112. Tao Y., Lu J., Du X., et al. Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells. BMC Cancer. 2012;12:619. doi: 10.1186/1471-2407-12-619. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 113. Wang R., Yuan W., Li L., et al. Resveratrol ameliorates muscle atrophy in chronic kidney disease via the axis of SIRT1/FoxO1. Phytother Res. 2022;36:3265–3275. doi: 10.1002/ptr.7499. [ DOI ] [ PubMed ] [ Google Scholar ] 114. Li J., Duan Q., Wei X., et al. Kidney-targeted nanoparticles loaded with the natural antioxidant rosmarinic acid for acute kidney injury treatment. Small. 2022;18 doi: 10.1002/smll.202204388. [ DOI ] [ PubMed ] [ Google Scholar ] 115. Hu X., Gan L., Tang Z., et al. A natural small molecule mitigates kidney fibrosis by targeting Cdc42-mediated GSK-3β/β-catenin signaling. Adv. Sci. 2024;11 doi: 10.1002/advs.202307850. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 116. Hickson L.J., Langhi Prata L.G.P., Bobart S.A., et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446–456. doi: 10.1016/j.ebiom.2019.08.069. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 117. Birn H. The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins. Am. J. Physiol. Ren. Physiol. 2006;291:F22–F36. doi: 10.1152/ajprenal.00385.2005. [ DOI ] [ PubMed ] [ Google Scholar ] 118. Kumar K., Bosch K., Vemuri V., et al. Withaferin A ameliorates ovarian cancer-induced renal damage through the regulation of expression of inflammatory cytokines. J. Ovarian Res. 2024;17:199. doi: 10.1186/s13048-024-01519-9. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 119. Liu C., Wang X., Wang X., et al. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics. 2022;12:7158–7179. doi: 10.7150/thno.78376. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 120. Bao J., Shi Y., Tao M., et al. Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy. Clin. Sci. 2018;132:2299–2322. doi: 10.1042/CS20180563. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 121. Schmucki K., Hofmann P., Fehr T., et al. Mammalian target of rapamycin inhibitors and kidney function after thoracic transplantation: a systematic review and recommendations for management of lung transplant recipients. Transplantation. 2023;107:53–73. doi: 10.1097/TP.0000000000004336. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 122. Ren H., Shao Y., Wu C., et al. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway. Mol. Cell. Endocrinol. 2020;500 doi: 10.1016/j.mce.2019.110628. [ DOI ] [ PubMed ] [ Google Scholar ] 123. Zheng C., Hou Y., Tsai K.W., et al. Resveratrol mitigates uremic toxin-induced intestinal barrier dysfunction in chronic kidney disease by promoting mitophagy and inhibiting apoptosis pathways. Int. J. Med. Sci. 2024;21:2437–2449. doi: 10.7150/ijms.100963. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 124. Aranda-Rivera A.K., Cruz-Gregorio A., Aparicio-Trejo O.E., et al. Sulforaphane protects against unilateral ureteral obstruction-induced renal damage in rats by alleviating mitochondrial and lipid metabolism impairment. Antioxidants. 2022;11:1854. doi: 10.3390/antiox11101854. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 125. Ren C., Bao X., Lu X., et al. Complanatoside A targeting NOX4 blocks renal fibrosis in diabetic mice by suppressing NLRP3 inflammasome activation and autophagy. Phytomedicine. 2022;104 doi: 10.1016/j.phymed.2022.154310. [ DOI ] [ PubMed ] [ Google Scholar ] 126. Wen S., Deng F., Li L., et al. VX-765 ameliorates renal injury and fibrosis in diabetes by regulating caspase-1-mediated pyroptosis and inflammation. J. Diabetes Investig. 2022;13:22–33. doi: 10.1111/jdi.13660. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 127. Dhorepatil A., Ball S., Ghosh R.K., et al. Canakinumab: promises and future in cardiometabolic diseases and malignancy. Am. J. Med. 2019;132:312–324. doi: 10.1016/j.amjmed.2018.10.013. [ DOI ] [ PubMed ] [ Google Scholar ] 128. Ridker P.M., MacFadyen J.G., Glynn R.J., et al. Inhibition of interleukin-1β by canakinumab and cardiovascular outcomes in patients with chronic kidney disease. J. Am. Coll. Cardiol. 2018;71:2405–2414. doi: 10.1016/j.jacc.2018.03.490. [ DOI ] [ PubMed ] [ Google Scholar ] 129. Wu Q., Guan Y., Zhang K., et al. Tanshinone IIA mediates protection from diabetes kidney disease by inhibiting oxidative stress induced pyroptosis. J. Ethnopharmacol. 2023;316 doi: 10.1016/j.jep.2023.116667. [ DOI ] [ PubMed ] [ Google Scholar ] 130. Li J., Lv L., Hu M., et al. Inhibition of N6-methyladenosine methylation of ASC by berberine ameliorates pyroptosis of renal tubular epithelial cells in acute kidney injury. Cell. Signal. 2025;131 doi: 10.1016/j.cellsig.2025.111732. [ DOI ] [ PubMed ] [ Google Scholar ] 131. Yosri H., El-Kashef D.H., El-Sherbiny M., et al. Calycosin modulates NLRP3 and TXNIP-mediated pyroptotic signaling and attenuates diabetic nephropathy progression in diabetic rats; an insight. Biomed. Pharmacother. 2022;155 doi: 10.1016/j.biopha.2022.113758. [ DOI ] [ PubMed ] [ Google Scholar ] 132. Zhao Z., Wu J., Xu H., et al. XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia–reperfusion injury. Cell Death Dis. 2020;11:629. doi: 10.1038/s41419-020-02871-6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 133. Jones G., Zeng L., Kim J. Mechanism-based pharmacokinetic modeling of absorption and disposition of a deferoxamine-based nanochelator in rats. Mol. Pharm. 2023;20:481–490. doi: 10.1021/acs.molpharmaceut.2c00737. [ DOI ] [ PubMed ] [ Google Scholar ] 134. Guerrero-Hue M., García-Caballero C., Palomino-Antolín A., et al. Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis-mediated cell death. FASEB J. 2019;33:8961–8975. doi: 10.1096/fj.201900077R. [ DOI ] [ PubMed ] [ Google Scholar ] 135. Wang Y., Quan F., Cao Q., et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis. J. Adv. Res. 2021;28:231–243. doi: 10.1016/j.jare.2020.07.007. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 136. Linkermann A., Bräsen J.H., Himmerkus N., et al. Rip1 (Receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 2012;81:751–761. doi: 10.1038/ki.2011.450. [ DOI ] [ PubMed ] [ Google Scholar ] 137. Hofmans S., Devisscher L., Martens S., et al. Tozasertib analogues as inhibitors of necroptotic cell death. J. Med. Chem. 2018;61:1895–1920. doi: 10.1021/acs.jmedchem.7b01449. [ DOI ] [ PubMed ] [ Google Scholar ] 138. Mandal P., Berger S.B., Pillay S., et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell. 2014;56:481–495. doi: 10.1016/j.molcel.2014.10.021. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 139. Xu C., Wang J., Suo X., et al. RIPK3 inhibitor-AZD5423 alleviates acute kidney injury by inhibiting necroptosis and inflammation. Int. Immunopharmacol. 2022;112 doi: 10.1016/j.intimp.2022.109262. [ DOI ] [ PubMed ] [ Google Scholar ] 140. Guo J., Hu J., Liu M., et al. Apigenin-mediated ESCRT-III activation and mitophagy alleviate LPS-induced necroptosis in renal cells. J. Agric. Food Chem. 2025;73:9906–9919. doi: 10.1021/acs.jafc.5c00627. [ DOI ] [ PubMed ] [ Google Scholar ] 141. Egbuna O., Zimmerman B., Manos G., et al. Inaxaplin for proteinuric kidney disease in persons with two APOL1 variants. N. Engl. J. Med. 2023;388:969–979. doi: 10.1056/NEJMoa2202396. [ DOI ] [ PubMed ] [ Google Scholar ] 142. Huber T.B., Walz G., Kuehn E.W. mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression. Kidney Int. 2011;79:502–511. doi: 10.1038/ki.2010.457. [ DOI ] [ PubMed ] [ Google Scholar ] 143. Ushijima H., Monzaki R. An in Vitro evaluation of the antioxidant activities of necroptosis and apoptosis inhibitors: the potential of necrostatin-1 and necrostatin-1i to have radical scavenging activities. Pharmacol. Rep. 2023;75:490–497. doi: 10.1007/s43440-023-00450-y. [ DOI ] [ PubMed ] [ Google Scholar ] 144. Xie J., Ye Z., Li L., et al. Ferrostatin-1 alleviates oxalate-induced renal tubular epithelial cell injury, fibrosis and calcium oxalate stone formation by inhibiting ferroptosis. Mol. Med. Rep. 2022;26:256. doi: 10.3892/mmr.2022.12772. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 145. Yang J.D., Lin S.C., Kuo H.L., et al. Imperatorin ameliorates ferroptotic cell death, inflammation, and renal fibrosis in a unilateral ureteral obstruction mouse model. Phytomedicine. 2024;135 doi: 10.1016/j.phymed.2024.156066. [ DOI ] [ PubMed ] [ Google Scholar ] 146. Pang Q., Wang P., Pan Y., et al. Irisin protects against vascular calcification by activating autophagy and inhibiting NLRP3-mediated vascular smooth muscle cell pyroptosis in chronic kidney disease. Cell Death Dis. 2022;13:283. doi: 10.1038/s41419-022-04735-7. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 147. Cheng Y., Lu Z., Mao T., et al. Magnoflorine ameliorates chronic kidney disease in high-fat and high-fructose-fed mice by promoting parkin/PINK1-dependent mitophagy to inhibit NLRP3/caspase-1-mediated pyroptosis. J. Agric. Food Chem. 2024;72:12775–12787. doi: 10.1021/acs.jafc.3c09634. [ DOI ] [ PubMed ] [ Google Scholar ] 148. Xiao L., Xu X., Zhang F., et al. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol. 2017;11:297–311. doi: 10.1016/j.redox.2016.12.022. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 149. Li J., Yang J., Xian Q., et al. Kaempferitrin attenuates unilateral ureteral obstruction-induced renal inflammation and fibrosis in mice by inhibiting NOX4-mediated tubular ferroptosis. Phytother Res. 2024;38:2656–2668. doi: 10.1002/ptr.8191. [ DOI ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. 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