Abstract Background and Aims Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality, but substantial heterogeneity among existing diagnostic and prognostic models results in inconsistent patient identification and risk assessment. We conducted a systematic head-to-head comparison of major ACLF diagnostic and prognostic models to evaluate concordance, short-term mortality prediction and clinical utility, with the goal of informing harmonization of ACLF assessment. Methods We analysed 3,370 patients with acute decompensation of cirrhosis in the COSSH cohort, with external validation in an independent Ambi-Spective cohort from India (n=2,055). Five ACLF diagnostic models were evaluated for identification of patients at risk of 28-day mortality. Reclassification was assessed using net reclassification improvement. Prognostic scores were compared using concordance index, integrated discrimination improvement, calibration, and decision-curve analysis. Results Diagnostic frameworks identified markedly different proportions of ACLF. A-TANGO and COSSH-ACLF classified the largest high-risk populations while maintaining substantial short-term mortality and balanced sensitivity–specificity profiles. Compared with COSSH-ACLF, A-TANGO improved net reclassification by 7.7%, with further gains versus EASL-CLIF (11.8%), APASL-ACLF (36.4%), and NACSELD-ACLF (45.9%). In the external cohort, A-TANGO and COSSH-ACLF showed similar discrimination and identified comparable proportions of patients. Combined application of the two models delineated three clinically meaningful strata, identifying a discordant intermediate-risk group with approximately 11% 28–day mortality. Among prognostic scores, COSSH-ACLF II and A-TANGO OF scores demonstrated strong and complementary performance across cohorts. Conclusions Outcome-anchored ACLF definitions converge in identifying patients at highest short-term risk across diverse populations. Alignment between A-TANGO and COSSH-ACLF, together with identification of an intermediate-risk phenotype, supports a data-driven framework for improving consistency and advancing global harmonization of ACLF diagnosis and risk stratification.

Rheumatoid arthritis (RA) is characterized by persistent synovitis. Conventional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) inadequately reflect synovial inflammation, particularly under interleukin-6 pathway inhibition. Pentraxin 3 (PTX3), an extrahepatic acute-phase protein produced in inflamed tissues, may better reflect local inflammation and angiogenesis in RA joints. We enrolled 80 RA patients and 80 age-sex-matched healthy controls. Clinical data, inflammatory markers, and disease activity scores (DAS28) were collected. Serum PTX3 levels were quantified by ELISA. Musculoskeletal ultrasound assessed bilateral wrists and metacarpophalangeal/proximal interphalangeal joints for synovial hypertrophy, effusion, color Doppler flow, and bone erosion. Eight patients received tocilizumab at baseline and week 12. PTX3 levels were significantly higher in RA patients than in controls. Serum PTX3 concentrations showed a progressive increase from remission to moderate-to-high disease activity groups. PTX3 showed no significant reduction after tocilizumab treatment. PTX3 correlated positively with CRP, ESR, DAS28-CRP, and rheumatoid factor, but not with anti-cyclic citrullinated peptide antibodies. PTX3 levels were elevated in patients with ultrasound-detected synovial blood flow compared to those without. Receiver operating characteristic analysis demonstrated superior diagnostic performance of PTX3 for predicting synovial blood flow compared to CRP and ESR. In multivariable logistic regression, PTX3 was the only significant predictor of synovial blood flow positivity. PTX3 demonstrates superior diagnostic performance over traditional inflammatory markers in detecting synovial vascularity and independently correlates with disease activity. PTX3 may serve as a valuable complementary biomarker for assessing local synovial inflammation and angiogenesis, particularly when conventional markers are inadequate.

Age-related decline in testosterone production, known as late-onset hypogonadism (LOH), is a common condition in aging males, but its underlying mechanisms remain incompletely understood. Here, we investigated whether disruption of mitochondrial fusion-fission balance contributes to age-related steroidogenic failure. Using aged mouse models and H₂O₂-induced senescent TM3 Leydig cells, we demonstrated that aging is associated with impaired mitochondrial function, characterized by fragmentation, decreased membrane potential (MMP), and reduced ATP production. This mitochondrial dysfunction was driven by an imbalance in mitochondrial dynamics, specifically a downregulation of the fusion protein Mitofusin 2 (MFN2) and a shift towards fission. Consequently, aged Leydig cells exhibited elevated oxidative stress, impaired mitophagy, and a significant decline in the expression of key steroidogenic enzymes, leading to reduced testosterone synthesis. Crucially, M1 treatment, a mitochondrial fusion promoter, reversed these aging phenotypes, restoring mitochondrial integrity and testosterone production. In contrast, MFN2 knockdown exacerbated them. Mechanistically, we found that MFN2's protective effects were independent of the SIRT1 pathway. However, the anti-aging benefits of SIRT1 activation were entirely dependent on MFN2. Our findings identify MFN2 as a central regulator of mitochondrial homeostasis in Leydig cells and establish mitochondrial dynamics imbalance as a key mechanism in age-related testosterone decline. Targeting mitochondrial fusion may represent a novel therapeutic strategy for LOH.

Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. SIGNIFICANCE:NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer.

ObjectivesCongenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder caused by mutations in NTRK1 that is characterized by pain insensitivity, anhidrosis, and recurrent fever. While genetic testing is the gold standard for CIPA diagnosis, the complexity of NTRK1 variants poses major challenges. Conventional sequencing that is limited to the coding regions of NTRK1 results in misdiagnoses or missed diagnoses in approximately 57% of patients. Accordingly, to improve the diagnostic efficiency of CIPA, we integrated whole-genome sequencing (WGS) with functional assays to identify deep intronic variants in NTRK1.MethodsAll 18 probands were initially screened using polymerase chain reaction (PCR) and Sanger sequencing covering all exons and canonical splice sites of NTRK1. For patients with only one identified pathogenic allele, WGS was performed to detect potential deep intronic variants. Candidate variants were functionally validated using reverse transcription PCR (RT-PCR) and T cloning sequencing to evaluate their effects on pre-mRNA splicing.ResultsTotal 23 pathogenic variants including 11 novel variants in NTRK1 were identified in 18 unrelated families with CIPA. Functional assays confirmed that five of these variants disrupted the normal splicing of NTRK1, resulting in multiple aberrant splicing patterns, including two exon-skipping events (c.428 + 273A>T, c.850 + 5G>A), three intron retentions (c.2187 + 389C>T, c.2188–459G>T, c.287 + 4A>C), and one pseudoexon insertion (c.2188–459G>T).ConclusionThis study expands the spectrum of pathogenic variants in NTRK1 and improves the genetic diagnosis of CIPA. The functional characterization of five novel non-canonical splicing variants provides deeper insight into the molecular pathogenesis of this disorder and establishes a foundation for future precision medicine approaches in CIPA.

Cancer-associated fibroblasts (CAFs) contribute to the metastatic progression of high-grade serous ovarian cancer (HGSOC), partly through the transfer of regulatory RNAs via exosomes. Here, we identify a circRNA, circMPP6 as a key pro-metastatic factor enriched in CAF-derived exosomes. circMPP6 is upregulated in metastatic HGSOC tissues and is associated with poor prognosis. In HGSOC cells, nuclear circMPP6 interacts with SFPQ and NONO to stabilize ADAM22 mRNA, whereas cytoplasmic circMPP6 binds EEF1A2 to enhance ADAM22 protein expression. Elevated ADAM22 levels activate TGF-β/Smad2/3 signaling via binding to ITGB1, promoting proliferation, migration, and invasion in vitro and metastasis in vivo. Silencing circMPP6 or disrupting the ADAM22 axis attenuates these oncogenic phenotypes. In CAFs, its loading into exosomes is mediated by hnRNPA2B1, enabling its transfer to adjacent tumor cells. These findings reveal a dual regulatory mechanism by which CAFs-derived exosomal circMPP6 enhances ADAM22 expression and activates pro-metastatic TGF-β signaling in HGSOC. Our study highlights circMPP6 as a potential therapeutic target and critical mediator of stromal-tumor communication in ovarian cancer metastasis.

Our prognostic model and mobile application allows for a comprehensive evaluation of the prognosis at multiple time points, thereby improving patient care and informing decisions regarding liver transplantation.

BACKGROUND:RGS5, the first gene identified in tumor-resident pericytes, plays a crucial role in angiogenesis. However, its effects on immunology and prognosis in human cancer are still mostly unknown. This study investigates the carcinogenic and immunological roles of RGS5 through a comprehensive pan-cancer analysis. METHODS:A standardized pan-cancer dataset for RGS5 was obtained from the public database. R software and relevant packages were utilized to analyze the oncogenic and immunological roles. Clinical samples and cellular experiments were conducted to validate RGS5 expression and its biological function in renal cancer. RESULTS:Bioinformatics analysis revealed that RGS5 is dysregulated in a variety of human malignancies and is significantly associated with patient prognosis. Additionally, RGS5 expression is closely linked to tumor heterogeneity and stemness indicators across different cancer types. Co-expression of RGS5 with genes involved in MHC, immune activation, immunosuppressive proteins, chemokines, and chemokine receptors was observed in various tumors. High expression of RGS5 predicts a good prognosis in patients with renal cancer. In the renal cancer cohort, RGS5 expression strongly correlated with the distribution of tumor-associated fibroblasts. Silencing RGS5 expression can affect the proliferation, migration, and invasion of renal carcinoma cells. CONCLUSIONS:RGS5 expression in tumors is intricately associated with various clinical features, particularly concerning tumor progression and patient prognosis.

TPS3680 Background: In pMMR unresectable metastatic colorectal cancer (mCRC), first-line standards combine cytotoxic chemotherapy with targeted agents (anti-EGFR or anti-VEGF). A chemotherapy-sparing strategy may be clinically relevant for selected patients, and biologically supported by potential synergy between EGFR inhibition and VEGFR blockade, with immunotherapy potentially enhanced by vascular normalization and microenvironment modulation. CONCEPT evaluates the safety and antitumor activity of cetuximab-β plus fruquintinib, with or without immune checkpoint blockade, as a first-line option in pMMR RAS/BRAF wild-type unresectable mCRC. Methods: CONCEPT is an open-label, multicenter, randomized phase II trial. Key eligibility: age 18–85, ECOG 0–1, histologically confirmed colorectal adenocarcinoma, pMMR, KRAS/NRAS/BRAF wild-type, unresectable metastatic disease, and ≥1 measurable lesion per RECIST v1.1. Planned N=70; randomization 1:1:1 to: A) cetuximab-β 500 mg/m² IV q2w + fruquintinib 5 mg PO QD (3 weeks on/1 week off); B) regimen A + PD-1 antibody 200 mg IV q4w; C) regimen A + PD-1/CTLA-4 antibody 5 mg/kg IV q4w. The study uses a seamless two-stage selection design: initial cohort (10 patients/arm) to assess early safety/activity, followed by expansion of one or two selected arm(s) (+20 patients per selected arm). Safety assessments are performed each cycle; radiologic tumor assessment is every 2 cycles. Primary endpoints: progression-free survival (PFS) and safety. Secondary endpoints include objective response rate (ORR), disease control rate (DCR) and overall survival (OS). The study is registered with ClinicalTrials.gov (NCI 07257653). Clinical trial information: NCI 07257653 .

Sepsis is increasingly viewed as a disorder of inflammatory, metabolic, and mitochondrial homeostasis, but the path from metabolic disturbance to regulated cell death (RCD) and organ injury remains incompletely defined. Human studies show clinically meaningful metabolic and bioenergetic heterogeneity, while experimental models link mitochondrial stress, inflammatory signaling, membrane disruption, and pathway-specific RCD to tissue dysfunction. This review asks how evidence can be moved from co-occurrence toward mechanism. We synthesize findings across systemic metabolic phenotypes, cell-intrinsic immunometabolism, mitochondrial stress, RCD execution, membrane failure, inflammatory cargo release, organ injury, and therapeutic relevance. Apoptosis has the strongest direct human support as a non-lytic route of immune-cell depletion and epithelial loss; pyroptosis, ferroptosis, necroptosis, and PANoptosis are supported mainly by sepsis-relevant models and remain context dependent. Stronger mechanistic inference requires aligned measurements of metabolic flux, mitochondrial state, RCD execution, membrane integrity, extracellular cargo, host-defense effects, and tissue outcomes within matched cellular, organ, model, and temporal contexts. This framework separates association, susceptibility, execution, inflammatory release, tissue consequence, and therapeutic relevance when interpreting links among metabolic stress, mitochondrial stress, and RCD in sepsis.

Chronic kidney disease (CKD) is increasing globally, presenting a critical health challenge. Renal fibrosis, the main pathological feature of CKD, is poorly understood and lacks targeted therapies. Here, we reveal that 5-methylcytosine (m5C) RNA methylation, primarily mediated by methyltransferase NSUN2, is significantly upregulated in renal fibrosis. Reduction of m5C RNA methylation levels upon NSUN2 loss attenuates fibrosis responses in cells, and specific knockout of NSUN2 in renal tubular epithelial cells alleviates renal fibrosis in several disease models. Mechanistically, NSUN2 methylates and stabilizes glycine amidinetransferase (GATM) mRNA. GATM exacerbates mitochondrial fission not only by directly binding to Drp1 but also through its product creatine, collectively driving the progression of renal fibrosis. We subsequently identify an inhibitor of NSUN2 that mitigates the progression of renal fibrosis. Collectively, our study demonstrates that targeting NSUN2-mediated m5C methylation of GATM mRNA therapeutically offers a promising strategy to slow the progression of CKD.

Background Emerging evidence indicates that SLC9A3R1 participates in oncogenesis, yet its prognostic relevance and immune-regulatory circuitry remain largely undefined. Methods A harmonized pan-cancer transcriptomic compendium was retrieved from public repositories, and the clinical cohort was employed for bladder-cancer validation of expression patterns and biological function. Cox regression models were constructed to quantify the prognostic impact of SLC9A3R1, while immunohistochemistry on paired tumor and adjacent urothelium was performed to corroborate protein abundance and clinicopathological associations. Oncogenic and immunological roles were subsequently interrogated using R v4.2.1 and associated bioinformatics packages. Results Pan-cancer profiling demonstrated widespread SLC9A3R1 dysregulation that correlated with patient outcome across malignancies. Moreover, its expression aligned with genomic-heterogeneity indices and stemness scores in multiple tumor entities. Immunohistochemistry confirmed elevated SLC9A3R1 protein in bladder tumors, and, within the same cohort, transcript abundance paralleled tumor-associated fibroblast distribution.SLC9A3R1 up-regulation sustains stem-like traits, migration, chemoresistance and immune escape, driving bladder-cancer aggressiveness. Conclusion SLC9A3R1 constitutes a multi-dimensional prognostic biomarker that integrates tumor progression, immune contexture and patient survival, thereby offering a rational target for precision oncology.

Expression of Concern for: '3D-printed dimethyloxallyl glycine delivery scaffolds to improve angiogenesis and osteogenesis', Zhu Min et al., Biomater. Sci., 2015, 3, 1236-1244, https://doi.org/10.1039/C5BM00132C.

BackgroundAlthough androgen receptor (AR)-targeted therapies have shown notable clinical efficacy in prostate cancer (PCa), the emergence of drug resistance remains a critical factor driving the clinical prognosis in castration-resistant prostate cancer (CRPC). Aberrant tumor lipid metabolism not only fulfills the energetic and biosynthetic requirements of rapidly proliferating cancer cells but also contributes to the development of therapeutic resistance.MethodsWe examined SOX8 expression in enzalutamide resistance (EnzR) cell lines and validated its association with tumor progression and clinical outcome. The malignant phenotypes related to EnzR were assessed in vitro using PCa cell lines with stable SOX8 overexpression or knockdown. Tumor xenografts were subsequently generated by inoculating the corresponding cell lines into nude mice. To elucidate the underlying mechanisms, we conducted RNA-seq, CUT&Tag, non-targeted metabolomics, and a series of molecular and biochemical assays.ResultsSOX8 expression was elevated in EnzR prostate cancer cell lines and positively correlated with poor patient prognosis. Reduced SOX8 expression enhanced cellular sensitivity to enzalutamide, whereas elevated SOX8 expression decreased drug responsiveness. Chromatin immunoprecipitations (ChIP) assays revealed that AR was enriched at the SOX8 promoter region and transcriptionally repressed SOX8. In vivo, stable SOX8 knockdown markedly suppressed tumor growth in nude mouse xenografts. Mechanistically, SOX8 promotes the EnzR by reprograming lipid metabolism and we identified carnitine palmitoyltransferase 2 (CPT2), a key enzyme in lipid metabolism, as a novel downstream target of SOX8. SOX8-driven lipid metabolic reprogramming promoted enzalutamide resistance through the SOX8/CPT2 axis.ConclusionsHigh SOX8 expression promotes EnzR in PCa, suggesting SOX8 as a potential therapeutic target. Our findings demonstrate that SOX8 drives EnzR by activating the SOX8/CPT2 axis, thereby inducing lipid metabolic reprogramming in PCa cells.

Background Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome involving dysfunction of multiple immune cell types.Objective This study aimed to comprehensively depict the dynamic trajectory of immune responses throughout the disease course of HBV-related ACLF (HBV-ACLF).Design Single-cell RNA sequencing and single-cell proteomics were performed on the peripheral blood mononuclear cells of 45 samples from 17 patients who were hospitalised (progressive/stable/recovering course of HBV-ACLF, 6/5/6) and 15 control subjects (liver cirrhosis, chronic hepatitis B and healthy controls, 5/5/5). Functional and mechanistic experiments were validated in vivo and in vitro.Results Single-cell multiomics analysis revealed specific changes in the peripheral immune response in ACLF. VCAN+CD14+-monocytes with activated interferon-stimulated genes and enhanced inflammatory functions, stimulated by HBV relapse and expanded in ACLF-1, fuelling early inflammatory storm. The subsequent apoptotic hepatocytes predominantly induce hyperinflammatory C-X-C motif chemokine receptor 2 (CXCR2)+-neutrophils and CD163+-monocytes, enriching in patients with progressive ACLF and serving as significant markers of disease deterioration. Cytotoxic T-cells were functionally impaired and significantly decreased in progressive patients. CXCR2+-neutrophils exhibited immunosuppressive activity and induced the exhaustion of cytotoxic T-cells. Pharmacological inhibition of CXCR2 significantly reduced neutrophils infiltration, restored cytotoxic T-cells and showed therapeutic effect in ACLF mice. Six immune cellular modules (CMs) were identified for patient stratification, with CM2 and CM6 showing strong predictive value for disease outcomes, and CM3 indicating a potential early therapeutic window.Conclusion Our longitudinal multiomics study revealed the dynamic evolution of the immune response in HBV-ACLF and characterised diverse immune patterns for the future precise management and therapeutic intervention.

The kidney is a primary target organ in systemic lupus erythematosus (SLE) and ANCA-associated vasculitis (AAV), which frequently manifest as lupus nephritis (LN) and renal AAV, respectively. A severe acute presentation of both diseases is rapidly progressive glomerulonephritis (RPGN), leading to rapid loss of renal function. However, the shared molecular mechanisms underlying this aggressive phenotype remain poorly defined. This study aimed to identify key biomarkers and pathological processes in acute autoimmune-related glomerulonephritis, with a focus on LN and AAV presenting as RPGN. Through comparative transcriptomic analysis of glomerular samples from patients with LN, AAV, and RPGN against healthy controls, we identified a total of 180 common differentially expressed genes, comprising 33 upregulated and 147 downregulated genes. Pathway analysis revealed enhanced immune and inflammatory responses, including neutrophil extracellular trap (NET) formation, accompanied by significant impairments in amino acid and fatty acid metabolism. A core set of 12 hub genes was identified, and network analysis suggested specific transcriptional and post-transcriptional regulatory axes. Immune infiltration analysis demonstrated a common pattern characterized by decreased resting immune cells and increased activated cells-including memory CD4 ⁺ T cells, NK cells, and mast cells-along with elevated monocyte levels, particularly in LN. Notably, epidermal growth factor (EGF) was significantly downregulated and strongly correlated with impaired renal function, demonstrating good diagnostic performance. These findings suggest that EGF may serve as a potential biomarker for LN and RPGN. This study provides the first systematic transcriptomic analysis of LN and AAV presenting as RPGN, highlighting enhanced inflammation (including NETosis) and dysregulated amino acid/fatty acid metabolism as key glomerular pathological features. Targeting EGF signaling and monocyte differentiation may offer novel therapeutic strategy for LN and AAV presenting as RPGN.

Background:Low birth weight (LBW) is a significant global health issue associated with an increased risk of long-term chronic diseases, yet its underlying molecular mechanisms remain unclear. DNA methylation serves as a crucial epigenetic mechanism for investigating these associations. Our study employed a unique model of birth weight-discordant monozygotic (MZ) twin neonates and a multi-level validation strategy to elucidate the mechanisms by which LBW affects immune function through DNA methylation at birth. Methods:We performed genome-wide DNA methylation profiling using methylated DNA immunoprecipitation sequencing (MeDIP-seq) on cord blood mononuclear cells (CBMCs) from monozygotic (MZ) twin pairs discordant for birth weight. After identifying the most significantly differentially methylated genes (DMGs), gene set linkage analysis (GSLA) was conducted to reveal key functional networks. Key DMGs were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to quantify transcript levels in CBMCs obtained from an independent neonatal cohort. Furthermore, we quantified the production of eight cytokines through in vitro immune stimulation assays in an additional independent neonatal cohort. We isolated lymphocytes and monocytes from cord blood and stimulated lymphocytes with phytohemagglutinin (PHA) and monocytes with lipopolysaccharide (LPS), respectively. Results:We identified top 50 DMGs significantly associated with LBW, among which 11 DMGs formed functional networks enriched in ten biological processes, with the interferon (IFN)-γ mediated immune response emerging as the predominant theme. We validated the messenger RNA (mRNA) levels of 11 DMGs in CMBCs and found significant changes in eight of these DMGs in LBW neonates. Regarding lymphocyte function in neonatal cord blood, baseline levels of IFN-γ mRNA and protein, as well as mRNA levels of IP-10, interleukin (IL)-4 and IL-10, were comparable between the LBW and NBW groups. After PHA stimulation, lymphocytes from LBW neonates produced significantly higher levels of IFN-γ and IP-10, but lower levels of IL-4 and IL-10, compared to those from NBW neonates (P<0.01). Additionally, monocytes from cord blood of LBW neonates consistently exhibited higher mRNA levels of IL-1β (P<0.001) and tumor necrosis factor (TNF)-α (P<0.05) than NBW neonates, both before and after LPS stimulation. Conclusions:A distinct genomic DNA methylation pattern in LBW neonates may underlie hyperresponsive IFN-γ signaling and a persistent pro-inflammatory immune phenotype. These findings indicate that epigenetic mechanisms that affect the immune response in individuals born with LBW may contribute to an increased long-term susceptibility to chronic inflammatory diseases. Future work is needed to establish the causal links among the observed methylation pattern associated with LBW, IFN‑γ hyperresponsiveness, and long‑term disease risk.

N6-methyladenosine (m6A), a well-known adenosine modification with newly recognized epigenetic functions, reportedly participates in the development of diverse liver diseases. Methyltransferases and demethylases, commonly referred to as "writers" and "erasers", respectively, play crucial roles in maintaining the balance of m6A modification. In liver disease research specifically, the functioning of these enzymes has piqued significant interest, revealing new perspectives on molecular pathogenic mechanisms. Writer proteins collaborate with co-factors to install m6A modification on RNA, while eraser proteins, exemplified by Fto and Alkbh5, remove modifications via different mechanisms. In liver diseases, the two are not simply antagonistic, but rather act jointly to affect disease progression. By focusing this review on the mechanisms of methyltransferases and demethylases in various liver diseases, we seek to enhance comprehension of m6A modification's role and support the advancement of related research and treatment strategies.