METTL3-mediated m6A modification in sepsis: current evidence and future perspectives.

METTL3-mediated m6A modification in sepsis: current evidence and future perspectives - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Epigenomics . 2025 Apr 19;17(9):611–623. doi: 10.1080/17501911.2025.2494983 Search in PMC Search in PubMed View in NLM Catalog Add to search METTL3-mediated m6A modification in sepsis: current evidence and future perspectives Zijun Wu Zijun Wu a Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China b Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China c Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China Find articles by Zijun Wu a, b, c , Changhong Miao Changhong Miao a Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China b Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China c Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China Find articles by Changhong Miao a, b, c, ✉ , Hao Zhang Hao Zhang a Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China b Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China c Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China Find articles by Hao Zhang a, b, c, ✉ Author information Article notes Copyright and License information a Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China b Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China c Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China ✉ CONTACT Changhong Miao [email protected] ✉ Hao Zhang [email protected] Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai 200032, China Received 2024 Dec 25; Accepted 2025 Apr 15; Collection date 2025. © 2025 Informa UK Limited, trading as Taylor & Francis Group PMC Copyright notice PMCID: PMC12143678  PMID: 40251974 ABSTRACT Sepsis, a severe systemic inflammatory condition triggered by infection, is associated with high morbidity and mortality worldwide. While medical diagnosis and treatment have advanced in recent years, a specific therapy remains unavailable. Recently, significant progress has been made in studying the epigenetic RNA modification N6-methyladenosine (m6A) and its core methyltransferase METTL3. The role of m6A in sepsis has also been increasingly elucidated. This review aims to explore the pathological mechanisms of sepsis and its relationship with m6A, focusing on the role of the key m6A writer, METTL3, in sepsis. KEYWORDS: Sepsis, METTL3, epigenomics, immune cells, organ injury 1. Introduction Sepsis is a severe systemic inflammatory response induced by infection. It was first characterized by Hippocrates as a dangerous, foul-smelling biological decay of the body [ 1 ]. For a long time, sepsis has remained a major threat to human health, contributing to high morbidity and mortality rates globally. An epidemiological statistic report from 2017 estimated approximately 48.9 million cases of sepsis annually, resulting in 11 million deaths, which account for 19.7% of global mortality [ 2 ]. In 2019, infection-related mortality increased to 13.7 million [ 3 ]. Another data analysis of neonatal sepsis incidence indicates that the number of neonatal sepsis and other neonatal infections rose from 5.59 million in 1990 to 6.31 million in 2019, representing an increase of 12.79% [ 4 ]. However, despite the high morbidity and mortality, sepsis therapy remains limited. The most recent international guidelines for managing sepsis and septic shock, published in 2021, recommend early liquid resuscitation and the preventive use of antibiotics [ 5 , 6 ]. These are primarily supportive measures, while premature application of broad-spectrum antibiotics may contribute to bacterial antimicrobial resistance [ 7 ]. Specific treatments for sepsis remain under development. Therefore, sepsis continues to pose a significant threat to human health, necessitating a deeper understanding of its pathogenesis, along with specific treatment strategies and preventive measures. Recently, epigenetic modifications have garnered significant attention in the study of disease mechanisms, including DNA methylation, histone modification, genomic imprinting, and chromosome remodeling. These modifications affect the characteristics and functions of genes by regulating the transcription or translation processes [ 8 ]. N6-methyladenosine (m6A), first discovered and proposed in 1974, is considered the most abundant RNA modification in eukaryotic cells [ 9 ]. It plays a crucial role in regulating gene expression, which controls RNA splicing, export, degradation, and translation. M6A is a dynamical and reversible process regulated by three regulatory protein types: methyltransferases (“writers”), demethylase (“erasers”), and recognition proteins (“readers”) [ 10 , 11 ]. As a major component of the m6A methyltransferase complex, METTL3 has increasingly gained attention as a research focus on sepsis. Therefore, this review aims to explore the potential of METTL3 in treating sepsis, highlighting its importance in developing novel treatment strategies. 2. Sepsis and N6-methyladenosine 2.1. Imbalance of inflammatory response in sepsis The third international consensus defines sepsis as “life-threatening organ dysfunction induced by a dysregulated host response to infection” [ 12 ], highlighting that the nonhomeostatic host response plays a more crucial role than the infection. An epidemiological study of sepsis reports that, between 1987 and 2000, gram-positive (G+) bacteria were the predominant pathogens in the United States, responsible for 52.1% of cases, while gram-negative (G-) bacteria accounted for 37.6% [ 13 ]. However, a study in 2009 involving 14,000 patients in intensive care units (ICU) across 75 countries revealed that gram-negative bacteria were isolated in 62% of patients with severe sepsis who had positive cultures, gram-positive bacteria in 47%, and fungi in 19% [ 14 ]. Staphylococcus aureus and Streptococcus pneumoniae are the most prevalent gram-positive isolates, while Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa predominate among gram-negative isolates [ 3 , 15 , 16 ]. These pathogens primarily affect the lungs, abdomen, and urinary tract [ 17 , 18 ]. In severe sepsis, the host response includes pro-inflammatory and anti-inflammatory responses. The imbalance between these responses is a critical factor in the pathogenesis of sepsis [ 19 ]. During the early stages of acute infection following the invasion, the pattern recognition receptors (PRRs) of the host detect pathogen-associated molecular patterns (PAMPs) and activate downstream signaling pathways, including nuclear factor-κB (NF-κB). This process triggers the release of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which enhances the recruitment and activation of inflammatory cells, thereby initiating an inflammatory response [ 19 ]. However, excessive pro-inflammatory responses can lead to tissue damage and organ dysfunction. Studies show that neutrophils from patients with sepsis release neutrophil extracellular traps (NETs). While they are effective in capturing and killing pathogens, they can also lead to adverse effects when overproduced. Excessive NETs may induce intravascular thrombosis and contribute to multiple organ failure [ 20 ]. To mitigate damage induced by excessive inflammation, the body activates anti-inflammatory mechanisms [ 21 ]. Anti-inflammatory cytokines, including IL-10, IL-4, and IL-37, inhibit the production of pro-inflammatory cytokines and modulate immune response. Immune cell death exacerbates immunosuppression, with apoptosis, pyroptosis, and ferroptosis being prominent. The expansion of regulatory cells, including Tregs and MDSCs, suppresses effector immune functions by releasing cytokine and upregulating checkpoint molecules (e.g., PD-1 and CTLA-4). Concurrently, reduced expression of HLA-DR impairs antigen presentation, while elevated immune checkpoint molecule expression induces T cell exhaustion. Nonetheless, in sepsis, the anti-inflammatory response can become excessive, leading to an immunosuppressive state [ 22 ]. Simultaneously, the pathogen activates neuroendocrine regulation, releasing acetylcholine to inhibit pro-inflammatory cytokine production [ 23 , 24 ]. It can also impair immune cell function and inhibit the pro-inflammatory gene transcription. The anti-inflammatory response places the host in an immunosuppression state, thereby increasing susceptibility to secondary infections [ 25 ]. 2.2. Dynamic m6A modifications The process of m6A modification in RNA is intricately regulated by three protein types: writers, erasers, and readers, each with distinct but interconnected functions. ( Table 1 ) M6A writers, such as methyltransferase-like protein 3/14 (METTL3/14), Wilms’ tumor-associated protein (WTAP), and Virlike m6A methyltransferase-associated (VIRMA), are responsible for catalyzing m6A methylation on RNA. METTL3 acts as the primary catalytic subunit, transferring methyl groups to adenine residues within a consensus sequence in RNA [ 26 , 49 ]. METTL14 improves the enzymatic activity of METTL3 by forming a heterodimeric complex, while WTAP anchors this complex in nuclear speckles and modulates its recruitment to specific RNA targets [ 28 ]. M6A erasers, including fat mass and obesity-associated protein (FTO) and ALKB homolog 5 (ALKHB5), are responsible for demethylating m6A-modified bases, reversing the modification. FTO removes m6A modifications from RNA, thereby modulating RNA metabolism and stability [ 34 ]. In contrast, ALKBH5 is crucial for processes such as mRNA splicing, export, and translation by demethylating nuclear RNAs [ 35 ]. M6A readers, such as YTH domain-containing family proteins (YTHDF1–3 and YTHDC1–2), directly recognize and bind to m6A marks, thereby influencing RNA metabolism. YTHDF1 promotes translation by interacting with translation initiation factors [ 36 ], while YTHDF2 facilitates RNA decay by targeting methylated transcripts to processing bodies [ 37 ]. YTHDF3 improves the synergistic actions of YTHDF1 and YTHDF2, modulating translation and decay pathways [ 38 , 39 ]. Nuclear readers, such as YTHDC1, mediate alternative splicing, RNA export, and chromatin silencing [ 30 , 40 ]. YTHDC2 improves translation efficiency and regulates RNA stability [ 41 , 42 ], while IGF2BP proteins improve mRNA stability by binding to m6A-modified transcripts [ 43 ] ( Figure 1 ). Accumulating evidence demonstrates that m6A modification plays a significant role in multiple physiological and pathological processes mediated by these three regulatory protein types, including cancer, cardiovascular diseases, pregnancy, and infertility. Table 1. The functional roles of m6A regulators in RNA metabolism. Categories M6A-related enzymes Location Function References Writers METTL3 Nucleus Catalyzing methyl-group transfer [ 26 , 27 ] METTL14 Nucleus Forming a heterodimer with METTL3 and enhancing its catalytic activity [ 26 , 27 ] WTAP Nucleus Promoting METTL3-METTL14 complex localization to nuclear speckles and modulating their recruitment to RNA targets [ 28 ] KIAA1429 Nucleus Preferentially mediating m6A modification in the 3’UTR and near stop codon, and affecting the selection of methylation sites [ 29 ] RBM15/RBM15B Nucleus Mediating m6A methylation of lncRNA XIST [ 30 ] ZC3H13 Nucleus Inducing the nuclear localization of Zc3h13-WTAP- Virilizer-Hakai complex [ 31 ] METTL16 Nucleus Functioning as a conserved U6 snRNA methyltransferase and regulating the abundance of intracellular SAM [ 32 , 33 ] Erasers FTO Nucleus Eliminating the m6A levels of targeted RNA by oxidative demethylation activity [ 34 ] ALKBH5 Nucleus Removing the m6A modification of nuclear RNA [ 35 ] Readers YTHDF1 Cytoplasm Augmenting RNA translation through interacting with eIF3 [ 36 ] YTHDF2 Cytoplasm Increasing the translation efficiency of RNA [ 37 ] YTHDF3 Cytoplasm Not only promoting the translation of methylated RNA in cooperation with YTHDF1, but also strengthening RNA decay mediated by YTHDF2 [ 38 , 39 ] YTHDC1 Nucleus Mediating alternative splicing, facilitating m6A-methylated RNA nuclear export, and promoting X chromosome genes transcriptional silencing mediated by XIST [ 30 , 40 ] YTHDC2 Cytoplasm Increasing the translation efficiency of RNA [ 41 , 42 ] IGF2BP1/2/3 Cytoplasm Fortifying RNA stability [ 43 ] HNRNPC Nucleus Participating in the pre-mRNA processing and functioning as a “m6A-switch” [ 44 , 45 ] HNRNPG Nucleus Modulating pre-mRNA alternative splicing and acting as a “m6A-switch [ 46 ] HNRNPA2B1 Nucleus Accelerating the processing of primary miRNA, regulating alternative splicing, and acting as a “m6A-switch” [ 47 , 48 ] Open in a new tab Figure 1. Open in a new tab General components and post-transcriptional regulation of m6A modification. M6A methylation is catalyzed by the writer complex including METTL3, METTL14, METTL16, WTAP, VIRMA, RBM15/15B, KIAA1429, and ZC3H13. The m6A modification is erased by demethylases including FTO and ALKBH5. The m6A-modified RNA reader proteins include YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, HNRNPC/N/A2B1. Reader proteins recognize m6A modification to regulate post-transcriptional processes including RNA splicing, pre-mRNA processing, pri-miRNA processing, nuclear transport, RNA stability, translation, and RNA degradation. 2.3. METTL3 in m6A METTL3, also known as MT-A70, was first isolated by Boker et al. from HeLa cells in 1997, confirming its role as an essential N6-adenosine methyltransferase subunit [ 50 ]. As the major catalytic enzyme in m6A methylation modification, METTL3 functions in different pathophysiological processes, including cell proliferation, cycle, apoptosis, migration, invasion, differentiation, and inflammatory response [ 51 ]. Despite being the most commonly discussed m6A methylase in the context of inflammation and inflammatory diseases, the role of METTL3 in sepsis has not been systematically elucidated. As immunological research on sepsis has advanced, the role of METTL3 in immune cell function and its mechanism in regulating the immune cell response to sepsis, alongside its involvement in sepsis-related organ damage, have become focal points of investigation in recent years. These findings underscore the crucial role of m6A modification in the pathophysiological process of sepsis and provide a scientific basis for employing METTL3 as a potential therapeutic target. Future studies should focus on further elucidating the function of METTL3 and exploring its potential in sepsis therapy. 3. METTL3 role in immune cell functions 3.1. METTL3 role in macrophage function Macrophages play an essential role in sepsis by participating in the initial clearance of pathogens and inflammatory response. However, they can also contribute to disease progression, owing to dysfunction during the middle and late stages of the condition. Macrophages can be polarized into M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes, each playing distinct roles at various stages of inflammation [ 52 ]. Early-phase macrophages recognize PAMPs via PRRs, such as Toll-like receptors (TLRs), enabling the phagocytosis and elimination of bacteria, viruses, and cellular debris. Macrophages secrete pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and interferons (IFNs), which help recruit neutrophils, monocytes, and other immune cells to the site of infection, thereby enhancing the defense mechanisms of the body [ 53 ]. Similarly, macrophages guide immune cells to the site of infection by releasing chemokines such as Chemokine (C-C motif) ligand 2 (CCL2) and Chemokine (C-X-C motif) ligand 8 (CXCL8). In some instances, macrophages protect host tissues by releasing anti-inflammatory factors, such as IL-10 and TGF-β, to limit the spread of inflammation [ 54 ]. As antigen-presenting cells (APCs), macrophages process pathogens for presentation to T cells, activating acquired immunity. However, during the immunosuppressive phase of sepsis, macrophages exhibit reduced phagocytosis and antigen-presenting capabilities, along with reduced secretion of inflammatory factors. This, along with macrophage apoptosis, can result in immune dysfunction and contribute to secondary infections. Recently, the role of m6A methylation modification in sepsis and related inflammatory diseases has garnered significant attention. Several studies have confirmed the essential role of METTL3 as a major methyltransferase for m6A modification in regulating macrophage function ( Figure 2 ). Chen Yao et al. demonstrated that recombinant thrombomodulin (rTM) reduced METTL3 levels by downregulating the expression of hypoxia-inducible factor-1α (HIF-1α) and inhibited the m6A modification of 6-phosphofructokinase, muscle type (PFKM) on mRNA, thereby reducing glycolysis and achieving anti-inflammatory reprogramming of macrophages. This provides a new approach to metabolic reprogramming for sepsis treatment [ 55 ]. In a related study, Yin [ 56 ] further demonstrates that METTL3 knockdown in macrophages could alleviate DSS-induced colitis by regulating glucose metabolism and inhibiting Th1 cell differentiation. This suggests that METTL3-mediated metabolic regulation could play a significant role in various inflammatory diseases [ 56 ]. From a signaling pathway perspective, Li et al. discovered that METTL3 modifies Braf mRNA via m6A to enhance its translation and activate the ERK signaling pathway, thereby exacerbating the inflammatory response [ 57 ]. In contrast, Du Xianrong further elucidated that METTL3 enhances the mRNA stability of T‐cell immunoglobulin mucin 1 (TIM1) via m6A modification – a process dependent on IGF2BP2 recognition. This METTL3/IGF2BP2/TIM1 axis significantly boosts macrophage M1 polarization and inflammatory cytokine factors, suggesting that METTL3 action may have complex downstream effects owing to the involvement of various signaling pathways [ 58 ]. At the cell fate regulation level, Chen demonstrates that METTL3 exacerbated macrophage pyroptosis and sepsis-associated acute lung injury by decreasing the stability of TTC4 [ 59 ]. Tong observed that METTL3 deletion reduced m6A modifications on IL-1 receptor – associated kinase 3 (IRAK3) mRNA, preventing its degradation and inhibiting the TLR4 signaling pathway, which ultimately attenuated macrophage activation and reduced resistance to pathogenic infections [ 60 ]. These findings indicate that METTL3 regulates the embodiment of macrophage function through different targets and pathways. Additional research is needed to confirm the synergistic effect of TTC4 and IRAKM by jointly knocking them down or creating a conditional knockdown of METTL3 model. Figure 2. Open in a new tab METTL3-mediated m6A modifications in innate and acquired cellular immune responses. (a) METTL3 regulates macrophage polarization and pyroptosis through metabolic reprogramming, signaling pathway activation and cell fate determination. (b) METTL3-dependent m6A modifications regulate iron death, pro-neutrophil migration, release of inflammatory factors, and exacerbation of the inflammatory response through different pathways. (c) Mettl3-dependent modification of m6a regulates in acquired immunity by promoting DCs maturation and differentiation to T cells through different signaling pathways. These studies highlight the multiple roles of METTL3 in macrophage function through m6A modification, including metabolic reprogramming, signaling pathway regulation, and cell fate regulation. While the specific mechanisms and biological effects vary, they collectively identify METTL3 as a critical node in regulating inflammatory responses and macrophage phenotypes, making it a potential target for treating sepsis and other inflammatory diseases. 3.2. METTL3 role in neutrophil function In humans, neutrophils constitute between 50% and 70% of circulating leukocytes and serve as the first line of defense against various infectious agents, including bacteria, fungi, and protozoa. Their primary functions include recruitment to infection sites, recognition and phagocytosis of microorganisms, and pathogen elimination through various cytotoxic mechanisms. These processes involve generating reactive oxygen species, releasing antimicrobial peptides, and forming neutrophil extracellular traps by expelling their nuclear contents. Recent studies demonstrate that neutrophils contribute to extracellular pathogen killing and interact with other immune cells, including dendritic cells (DCs), lymphocytes, and NK cells [ 61 , 62 ]. This indicates that neutrophils may play an increasingly critical role in inflammatory response, underscoring the need for further investigation and offering novel insights into immunotherapy development. Recent studies highlight the significant role of NETs in inflammatory diseases, especially in regulatory mechanisms associated with iron death and cell injury. Several studies have focused on m6A modification as an epigenetic regulatory mechanism, exploring the function of METTL3 as a key enzyme and its downstream effects ( Figure 2 ). A study by Zhang Hao demonstrates that NETs increase hypoxia-inducible factor-1α (HIF-1α) expression through the activation of METTL3-mediated m6A modification and cause mitochondrial metabolic reprogramming via an IGF2BP2-dependent mechanism, thereby exacerbating iron death and worsening lung injury [ 63 ]. In their other study, NETs regulate GPX4 expression through m6A modification, thereby inducing iron death. Furthermore, the critical role of the TLR9/MyD88/NF-κB signaling pathway in upregulating METTL3 was identified [ 64 ]. The two studies collectively highlight the crucial regulatory function of NETs in iron death, although they do so by targeting different mechanisms and signaling pathways. Luo et al. demonstrate that METTL3 boost TLR4 protein levels, promoting neutrophil migration and the secretion of pro-inflammatory factors by enhancing the translation efficiency and stability of TLR4 mRNA [ 65 ]. This finding suggests that MRTTL3 not only regulate cell metabolism and death through m6A modification but also play a crucial role in the functional regulation of immune cells. 3.3. METTL3 role in DCs function DCs play a critical role in orchestrating immune response to inflammation, serving as a link between innate and adaptive immunity. They are essential in enhancing immune defenses and maintaining immune tolerance. Early DCs differentiate from immature to mature cells in response to recognizing pathogens or inflammatory mediators. Mature DCs then migrate to lymph nodes, where they upregulate major histocompatibility complex (MHC) molecules and co-stimulatory molecules such as CD80 and CD86, enabling the delivery of endogenous or exogenous antigens to T cells via MHC-I or MHC-II molecules, thereby promoting T-cell differentiation and enhancing the immune response [ 66 , 67 ]. Dysregulation of DC migration can lead to improper localization or activation of DCs, potentially causing an imbalance in immune response. Recently, considerable research has highlighted the critical role of METTL3 and its mediation of m6A modifications in acquired immunity ( Figure 2 ). Wang et al. reveal that METTL3 promotes the phenotypic maturation and functional enhancement of DCs by enhancing the translation of transcripts correlated with immune activation, such as CD40, CD80, and Tirap [ 68 ]. This enhances the phenotypic maturation and functionality of DCs through the TLR4/NF-κB signaling pathway, consequently resulting in a marked increase in cytokine production and T-cell activation. Similarly, Wu et al. observed that METTL3 knockdown induces a tolerogenic phenotype in DCs, characterized by reduced expression of molecules such as MHCII, CD80, and CD86, along with decreased secretion of pro-inflammatory cytokines, including IFN-γ and IL-12, which resulted in a significant decrease in their proliferative and activating effects on T cells [ 69 ]. These findings underscore the critical role of METTL3 in regulating DC immunoreactivity. 3.4. METTL3 role in T cell function T cells are activated into two interacting subtypes, namely CD4 + and CD8 + , when the T cell antigen receptor (TCR) complex encounters peptide antigens presented to them by antigen presenting cells (APC). CD8 + T cells are cytotoxic T lymphocytes (CTLs), whereas CD4 + T cells are T helper cells (Th) [ 69 ]. Among these, Th17, CD4 + subpopulations, is primarily responsible for secreting IL-17, which is crucial in antimicrobial immunity and inflammatory processes [ 70 ]. Wei demonstrated the involvement of the METTL3/miR-338-3p/Dusp16/p38 signaling pathway in DC-driven pathological responses associated with Th17 [ 71 ]. This finding indicates that METTL3 is a crucial regulator of DC maturation and a key contributor to the pathological mechanisms underlying Th17-related autoimmune diseases. This highlights potential Th17-mediated therapeutic targets. Similarly, Fang et al. investigated METTL3 in intestinal epithelial cells and observed a substantial decrease in its expression during acute enteritis. METTL3 knockdown results in the significant activation of pyroptosis in intestinal epithelial cells, accompanied by aberrant CD4 + T cell proliferation and CD8 + T cell depletion [ 72 ]. These studies underscore the significance of METTL3 in DC maturation, T-cell activation, and immune-mediated disease ( Figure 2 ). 4. METTL3 affects sepsis-related organ dysfunction 4.1. METTL3 affects SICM Sepsis-induced cardiomyopathy (SICM), also known as sepsis-induced myocardial dysfunction (SIMD), is a transient cardiac dysfunction increasingly recognized in patients with sepsis. During sepsis, the release of inflammatory mediators induces mitochondrial dysfunction, consequently leading to vascular endothelial damage. Furthermore, autonomic dysfunction causes an imbalance in myocardial oxygen supply and demand, ultimately resulting in interstitial inflammation, fibrosis, and reduced myocardial compliance. These changes impair the pumping efficiency of the heart and worsen the prognosis of the patient [ 73 ]. Shen et al. reveal that METTL3 increased the methylation level of SLC7A11 mRNA through m6A modification, which is subsequently recognized and degraded by the m6A-reading protein YTHDF2. This process inhibits SLC7A11 protein expression, thereby exacerbating ferroptosis [ 74 ]. Liang et al. reveal that sepsis-induced METTL3 overexpression promotes the maturation of pri-miR-193a via m6A modification, resulting in miR-193a enrichment, BCL2L2 expression inhibition and activation of caspase-3 apoptotic pathway. This further exacerbates apoptosis and inflammatory response in cardiomyocytes. This finding underscores the crucial function of the METTL3/m6A/miR-193a/BCL2L2 signaling pathway in the etiology of SICM [ 75 ]. Moreover, FTO exerts a significant inhibitory effect on cardiomyocyte ferroptosis and enhances myocardial function by regulating the m6A modification of the key gene BACH1 [ 76 ]. A significant correlation exists between cuproptosis-related genes such as VEGFA and CP and the expression levels of m6A-modified genes， suggesting that m6A modification may influence septic myocardial injury by regulating copper metabolism [ 77 ]. In conclusion, m6A modification plays a multifaceted role in the pathogenesis of SICM ( Figure 3 ). Therefore, developing strategies to target and regulate this modification presents a promising approach for future therapeutic interventions in SICM. Figure 3. Open in a new tab METTL3-mediated m6A modifications in sepsis-associated organ dysfunctions. RNA m6A modifications are involved in the pathogenesis of multiple organ injury during sepsis. 4.2. METTL3 affects sepsis-related ALI Recently, the mechanism of METTL3 in sepsis-related acute lung injury (ALI) has become a major research focus, with several studies highlighting its essential involvement in regulating inflammatory response, ferroptosis, and cellular injury. Chen Yi et al. demonstrate through in vitro and in vivo experiments that METTL3 protect vascular endothelial barrier function and reduces inflammatory response by inactivating the Trim59-related NF-κB pathway. This is the first direct evidence of the protective role of METTL3 in inhibiting inflammation [ 78 ]. Similarly, Jin Ai et al. demonstrate that METTL3 facilitates mRNA destabilization by adding m6A modification to GATA6 mRNA, consequently inhibiting the release of pro-inflammatory factors via GATA6 and suppressing the inflammatory cascade triggered by NF-κB. These findings further validate the crucial role of METTL3 in the NF-κB signaling pathway [ 79 ]. Wu et al. further conducted research on the molecular mechanism of the lactate-histone lactylation-METTL3-m6A modification-ACSL4 axis. Their findings demonstrate that lactate improves the transcriptional activity of METTL3 through p300-dependent H3K18la, regulates the mRNA stability of ACSL4, and promotes ferroptosis through a YTHDC1-dependent pathway. Furthermore, the study indicates that the METTL3 inhibitor STM2457 could effectively block lactate-induced ferroptosis, suggesting a potential molecular target for treating septic lung injury [ 80 ]. Moreover, research has examined the correlation between NETs and METTL3. Zhang et al. reveal that NETs activate METTL3-mediated m6A modification to stimulate HIF-1α expression, which then triggers mitochondrial metabolic reprogramming through an IGF2BP2-dependent mechanism [ 63 ]. This critically exacerbates ferroptosis and lung injury. Qu et al. elucidated another facet of the function of NETs, demonstrating that METTL3 activated by NETs inhibits autophagic flux and induces cellular injury by reducing the stability of Sirt1 mRNA [ 81 ]. These studies highlight the complex functions of METTL3 in sepsis-associated ALI from multiple perspectives, including the regulation of the inflammatory response, promotion of iron-dependent cell death, and inhibition of autophagy ( Figure 3 ). These findings reveal the multiple roles of METTL3 in sepsis-associated ALI and elucidate potential therapeutic targets, thereby laying a groundwork for future in-depth research and clinical applications. 4.3. METTL3 affects S-AKI Sepsis-associated acute kidney injury (S-AKI) is a common and potentially fatal complication in hospitalized and critically ill patients, with approximately two-thirds of those with septic shock [ 82 , 83 ]. Consequently, understanding the mechanism of METTL3 in S-AKI could provide a vital theoretical foundation for therapeutic strategies targeting m6A modification ( Figure 3 ). Pan et al. reveal the critical role of the METTL3/lncRNA 121,686 (or hsa-lncRNA 520,657)/miR-328-5p/HtrA3 pathway in the pathogenesis of AKI. In their AKI model, METTL3-dependent m6A modification led to the upregulation of long-stranded non-coding RNA (lncRNA) 121,686 expression in mice and its homologous hsa-lncRNA 520,657 in humans. The knockdown of lncRNA 121686 or the inhibition of METTL3 expression leads to a significant reduction in the severity of ischemia, sepsis, and vancomycin-induced AKI [ 84 ]. Wang et al. discovered a crucial increase in METTL3 expression across several AKI models, including murine models and human tissue samples. This increase enhances inflammation and programmed cell death by improving m6A modification and stability of TAB3 mRNA, a process mediated by IGF2BP2. Furthermore, the authors identified and validated a novel METTL3 inhibitor, Cpd-564, which demonstrates critical protective effects in a mouse model of AKI [ 85 ]. Additionally, Zhao et al. reveal that ALKBH5 contributes to the development of lipopolysaccharide (LPS)-induced epithelial-mesenchymal transition (EMT) and renal fibrosis by reducing the m6A modification of miR-205-5p and increasing DDX5 expression [ 86 ]. Yang et al. examined the protective role of FTO in inhibiting autophagy in SA-AKI by regulating the SNHG14/miR-373-3p/ATG7 axis [ 87 ]. Huang et al. adopted a different approach, examining the role of WTAP. Their findings demonstrate that WTAP activates the NF-κB and JAK2/STAT3 signaling pathways by promoting m6A modification of LMNB1, which subsequently leads to inflammation, mitochondrial damage, and iron-dependent apoptosis in renal tubular epithelial cells [ 88 ]. The collective findings of these studies highlight the multifaceted functions of m6A modifications in SA-AKI, thereby providing novel avenues for developing future therapeutic strategies. 4.4. METTL3 affects SAE Sepsis-associated encephalopathy (SAE) denotes an acute brain dysfunction triggered by systemic inflammation affecting the central nervous system sepsis. The incidence of SAE is approximately 70%, with a high mortality rate and significant disability [ 89 ]. The systemic inflammatory response in patients with sepsis yields the production of endotoxins and pro-inflammatory cytokines that enter the central nervous system via transcellular transport, activate cerebral microvascular endothelial cells and microglia, and increase the permeability of the blood-brain barrier (BBB) [ 90 ]. Concurrently, endothelial cell mitochondrial dysfunction exacerbates oxidative stress, further disrupting barrier integrity. M6A modifications have been linked to the pathogenesis of SAE ( Figure 3 ). The diversity of the gut microbiota in patients with SAE is diminished from those without and is concomitant with increased METTL3 expression and decreased FTO expression. Notably, enriched Acinetobacter in SAE patients positively correlated with METTL3 expression, suggesting that m6A modifications regulate gut microbiota during SAE [ 91 ]. Zhang et al. reported for the first time that METTL3 enhanced GOT1 mRNA stabilization, promoting neuronal injury. This mechanism integrates m6A modification with the GOT1-mediated glutamate metabolism pathway and provides new insights into the pathogenesis of SAE [ 92 ]. Furthermore, the knockdown of YTHDF1 in macrophages enhances sTie2 expression, contributing to the preservation of endothelial cell integrity within the pulmonary vascular system and the BBB. This, in turn, mitigates brain injury during sepsis [ 93 ]. Recognizing the crucial importance of BBB integrity and neuronal survival in septic encephalopathy development, upcoming research should focus on analyzing the molecular pathways related to m6A modification influencing cerebrovascular endothelial cell function. Additionally, efforts should be made to establish the epigenetic regulatory network that supports neuronal mitochondrial homeostasis and the cellular response to oxidative stress. This will facilitate precise intervention of septic brain injury. 4.5. METTL3 affects S-ALI Sepsis-induced acute liver injury (S-ALI) is a major contributor to mortality in patients with sepsis [ 94 ] observed in approximately 34% of adult patients. Furthermore, the mortality risk for patients with SALI is found to be nearly 40% higher than that of other patient populations [ 95 , 96 ]. The prevailing hypothesis concerning the etiology of liver injury in sepsis is its association with abnormal macrophage polarization and function, pro-inflammatory factor release, and cellular pyroptosis and iron death [ 97 ]. In recent years, research has identified the gut – liver axis as a significant component in the pathophysiology of sepsis. The destruction of the intestinal barrier allows pathogenic bacteria to invade, disrupting the homeostasis of bacterial flora. This, in turn, facilitates the entry of bacteria and their by-products into the bloodstream via the portal vein and the lymphatic system. These bacteria can affect bile acid metabolism, leading to cholestasis and hepatocyte toxicity [ 98 , 99 ]. In addition, sepsis-induced inflammation and microcirculatory dysfunction increase the likelihood of hepatic ischemia-reperfusion injury [ 100 ]. These factors co-exacerbate liver damage. Despite the available data on the role of m6A modifications in regulating gene expression, there remain significant gaps in the molecular mechanisms involved in the pathology of SALI ( Figure 3 ). M6A modification may aid the development of SALI by regulating the immunometabolic network of the gut-hepatic axis and the phenotypic switching of macrophages. Future studies should focus on addressing the following: 1) Resolving the trans-organ regulatory mechanisms underlying m6A modification in intestinal barrier dysfunction and intrahepatic inflammatory response; 2) elucidating the epigenetic regulatory role of m6A modification on macrophage polarization status; 3) exploring the potential value of m6A-modifying enzymes (e.g., METTL3 and FTO) as intervention targets. These studies will provide insights into the epigenetic regulatory network of SALI and facilitate the development of therapeutic strategies based on m6A modifications. 5. Therapeutic implication of METTL3 The study of METTL3 expression and its associated pathological processes in sepsis provides insights into developing effective pharmacological agents and the formulation of novel diagnostic strategies. ( Table 2 ). Table 2. Effects of natural products, synthetic compounds, and biological agents on METTL3. Category Examples Effect of METTL3 In vivo In vitro Reference Natural Products Emodin Upregulation LPS-treated 1321N1 cells [ 101 ] Cinnamaldehyde Upregulation Free fatty acids induced AML12 [ 102 ] Total flavones of Abelmoschus manihot Upregulation High glucose treated MPC-5 cells [ 103 ] specnuezhenide Upregulation Monosodium iodoacetate induced TMJ OA mice TNF-α induced chondrocytes [ 104 ] Resveratrol Downregulation Mice fed with high-fat diet [ 105 ] Resveratrol Upregulation Mice fed with high-fat diet [ 106 ] Synthetic compounds Cpd-564 Downregulation Cisplatin- and I/R-induced AKI mouse model Cisplatin-treated HK2 cells [ 85 ] Cpd-564 Downergulation De-ovulated (OVX)-induced osteoporotic rats Senescent osteoblasts [ 107 ] S-adenosylhomocysteine (SAH) Downregulation Monosodium iodoacetate induced TMJ OA mice TNF-α induced chondrocytes [ 104 ] Methylation inhibitor cycloleucine No effects Collagenase-induced OA mice [ 108 ] Methyl donor betaine No effects Collagenase-induced OA mice [ 108 ] WD6305 Downregulation Mono-Mac-6 and MOLM-13 [ 109 ] F039–0002 and 7460–0250 Downregulation dss-induced colitis mice BMDMs [ 110 ] Biological agents miR-1208 within hucMSCs-EVs Downregulation DMM-induced OA knee mice model LPS and nigericin-treated THP-1 [ 111 ] STM2457 Downregulation MLL-AF9/Flt3Itd/ + and NSG mice MOLM-13 [ 112 ] STM2457 Downregulation CLP mouse model MLE12 [ 80 ] Open in a new tab Natural compounds have been utilized for the specific targeting of METTL3. Wu et al. discovered that administering resveratrol to mice on a high-fat diet significantly increased METTL3 levels within liver tissues, along with enhanced expression of genes involved in fatty acid oxidation, such as PPARα and its target genes. Additionally, they observed a decrease in hepatic m6A RNA methylation and a reduction in hepatic fat accumulation [ 106 ]. Similarly, Izquierdo et al. report that resveratrol suppressed the expression of METTL3 and FTO in the hippocampal region of first-generation progeny mice, significantly increasing the level of m6A modification and conferring a neuroprotective effect on cognitive function [ 105 ]. Wang et al. [ 101 ] and Xu et al. [ 102 ] verified the regulation of METTL3 by various compounds (rhodopsin and cinnamaldehyde) in astrocyte and hepatocyte models, respectively, highlighting their protective effects in anti-inflammation and steatosis. Liu et al. discovered in vitro that total flavonoids from Marshmallow (TFA) enhance m6A modification of phosphate and tension homology (PTEN) mRNA, alleviating high-glycemic-induced thermal apoptosis and podocyte injury, with potential protective effects against diabetic nephropathy [ 103 ]. Wei et al. [ 104 ] report that the natural compound specnuezhenide (Spe) upregulates the expression of osteogenesis-related genes, such as Osteocalcin and RUNX2, by enhancing METTL3 expression and activity, causing the upregulation of m6A modification and enhancing the bone-promoting and angiogenic effects of LEPR + BMSCs [ 104 ]. Zhou et al. [ 96 ] further elucidated the therapeutic effects of MSC-derived extracellular vesicles on osteoarthritis, suggesting a regulatory role of m6A modification in bone and joint diseases [ 111 ]. Additionally, several small molecule inhibitors have shown significant therapeutic potential in targeting METTL3. Du et al. designed a small molecule compound, WD6305, based on PROTAC technology, which leads to a significant reduction in the expression of METTL3 and METTL14, along with a decrease in m6A modification level via protein degradation [ 109 ]. Similarly, METTL3 inhibitors developed by Yin et al. proved effective in alleviating inflammatory symptoms in a mouse model of DSS-induced colitis, further validating the critical role of METTL3 regulation in immune inflammation [ 110 ]. Yankova [ 112 ] and Wu et al. [ 80 ] examined the inhibition of STM2457 to impede acute myeloid leukemia and iron death-related processes in septic lung injury, respectively, while Cpd-564 [ 107 ] and PROTAC technology [ 85 ] developed by Liu and Wang demonstrate advantages in treating anti-aging bone metabolism and acute kidney injury, respectively. Cycloleucine reduces IL-8 and IL-6 and promotes type II collagen levels in OA cartilage tissues [ 102 ], while the METTL3 inhibitor S-Adenosylhomocysteine (SAH) significantly alleviates the bone-enhancing effects of Spe, offering a new direction for the treatment of TMJ OA [ 104 ]. These studies highlight the multifunctionality and complexity of m6A modification and suggest that regulating the expression or activity of METTL3 can provide therapeutic benefits for inflammation, metabolic disorders, neurodegenerative diseases, and bone and joint diseases. This presents a multifaceted approach for further research in m6A modification, thereby laying a crucial foundation for developing precision therapeutic strategies based on m6A modification. Research on targeting and regulation of METTL3 remains in its early stages, and several challenges remain to be fully addressed. As previously demonstrated, the function of METTL3 is paradoxical in different tissues. The effect of resveratrol [ 105 , 106 ] on METTL3 appears to have yielded equivocal results in disparate studies, highlighting the intricacy and heterogeneity of its function in different tissues. The potential value of targeting METTL3 in the treatment of metabolic diseases and neurological disorders remains to be fully elucidated. Further research is warranted to optimize the application of this target through mechanistic studies and validation of preclinical findings. These observations suggest that targeting strategies should be precise, as a single modulation (e.g., systemic inhibition or activation) may lead to pleiotropic side effects. Most existing studies focus on the static regulation of METTL3, although m6A modification is dynamic and reversible. This suggests that METTL3‘s regulatory role differs during the early and chronic phases of inflammation, necessitating intervention strategy adaptation according to disease progression. Furthermore, there exist barriers to the clinical translation of these findings. Existing studies have largely been based on mouse models; the human m6A modification profile differs from that of rodents, and as such, the target’s conservation in humans requires validation. Some compounds (e.g., Spe [ 104 ]) have demonstrated suboptimal stability in vivo , necessitating the development of novel delivery systems (e.g., nanocarriers) to enhance bioavailability 6. Future perspective This review systematically examines the pathological mechanisms of sepsis and its progression through m6A epigenetic modifications, with a particular focus on the core methyltransferase METTL3. By reviewing recent studies, we observed that METTL3 not only plays a crucial role in regulating immune cell function but also influences sepsis-related organ damage via metabolic reprogramming, pathway modulation, and regulation of cell fate. Notably, METTL3 regulates macrophage glycolysis, improves M1 polarization, and impairs M2 polarization via m6A modification, offering new therapeutic insights into macrophage metabolic reprogramming. Additionally, METTL3 worsens lung injury and contributes to ferroptosis by modulating NETs, revealing its complex role in sepsis-related organ damage. These innovative studies not only enhance the understanding of sepsis pathogenesis but also provide a foundation for developing epigenetic targets. Based on the analyses presented in this review, future studies should prioritize the following directions: First, the specific roles of m6A modifications in various immune cells should be investigated by employing multi-omics techniques along with single-cell sequencing approaches. Second, while small molecule inhibitors targeting METTL3, such as STM2457, have demonstrated potential in sepsis-induced acute lung injury models, their safety, specificity, and long-term effects require comprehensive validation. Third, investigating the synergistic regulation of m6A modification with other epigenetic modifications, such as histone acetylation, could inspire novel multidimensional therapeutic strategies. Future in-depth research will further advance the application of epigenetics in the precision treatment of sepsis, potentially improving the clinical outcome and benefiting public health. Acknowledgments We would like to acknowledge that we were unable to cite many references due to space constraints. Funding Statement This review was supported by the National Natural Science Foundation of China (No. 82472183), Shanghai Rarsing Star Program (24QA2707800) Shanghai Pujiang Talents Program (No. 21PJD013).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author contributions Zijun Wu wrote the main manuscript. Hao Zhang and Changhong Miao conducted manuscript editing and revision. Disclosure statement The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflicts with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Medical writing support was provided by Jenny Ann and Zaid from Editage and was funded by National Natural Science Foundation of China (No. 82472183). Article highlights m6A remodeling is one of the hallmarks of sepsis regulated synergistically or individually by various epigenetic factors. METTL3 mediated m6A modification pathway involves in the immune remodeling of sepsis and plays a role in different stages of septic immunity. Preclinical interventions targeting m6A modifications have exhibited effectiveness in treating sepsis and relieving multiple organ dysfunction due to sepsis. References Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Funk DJ, Parrillo JE, Kumar A.. Sepsis and septic shock: a history. Crit Care Clin. 2009;25(1):83–101, viii. doi: 10.1016/j.ccc.2008.12.003 [ DOI ] [ PubMed ] [ Google Scholar ] 2. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the global burden of disease study. 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