Objective To assess the association between comorbid Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and the risk of developing severe liver disease and cardiovascular disease (CVD) in patients with Chronic Hepatitis B (CHB). Methods CHB Patients were continuously recruited from 2012 to 2022 using the electronic medical record system, and divided into CHB-no MASLD and CHB-MASLD groups. Follow-up continued until January 2024, aiming to compare differences of cumulative incidence between the two groups and to analyze associated risk factors. Results 8,052 patients were included with a median follow-up of 3.9 years. Compared with CHB-no MASLD group, MASLD was independently associated with a 39% lower risk of severe liver disease (adjusted hazard ratio [aHR]=0.61, 95% confidence interval [CI] 0.49-0.76, p < 0.001), with similar effects in cirrhosis (aHR=0.61, 95% CI 0.45-0.82, p= 0.001) and hepatocellular carcinoma (HCC) (aHR=0.57, 95% CI 0.41-0.80, p = 0.001). Stratified analyses indicated the protection effect was more significant in the HBsAg-positive group. Conversely, MASLD was associated with higher CVD risk (aHR=1.16, 95% CI 0.96-1.41, p= 0.130), driven by coronary artery disease (aHR=1.91, 95% CI 1.34-2.74, p < 0.001) and arrhythmia (aHR=1.44, 95% CI 1.00-2.08, p= 0.053). These findings remained consistent after propensity score matching (PSM). Conclusion MASLD may reduce the risk of severe liver disease through certain mechanisms, yet it also constitutes a risk factor for CVD, particularly among HBsAg-positive patients.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with limited pharmacological treatments. Dietary fibre, known for its potential protective effects against NAFLD, may influence hepatic lipid metabolism through gut microbiota modulation and improved insulin sensitivity. However, the interaction between dietary fibre intake and genetic predisposition in NAFLD remains unclear. This study aimed to explore the association between dietary fibre intake and NAFLD risk, and whether genetic factors modulate this relationship. We conducted a prospective cohort study using data from the UK Biobank, including 424,008 participants without baseline liver disease. Dietary fibre intake was assessed using a validated food frequency questionnaire, and genetic risk was evaluated using a genetic risk score (GRS) for hepatic fat content. Cox proportional hazards models were used to estimate hazard ratios (HRs) for NAFLD risk, adjusting for covariates such as age, sex, BMI, and lifestyle factors. Over an average follow-up of 12.1 years, 4662 incident NAFLD cases were identified. Higher dietary fibre intake was inversely associated with NAFLD risk (HR for highest vs. lowest quintile: 0.70, 95

BACKGROUND:Notch signaling regulate innate immune cell function during tissue injury, while thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome activation drives lung inflammation. However, the role of Jagged1-mediated macrophage Notch1 signaling in regulating TXNIP/NLRP3 inflammasome function in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. METHODS:To investigate this, we utilized wild-type (WT), floxed Notch1 (Notch1FL/FL) and myeloid-specific Notch1 knockout (Notch1M-KO) mice were intratracheal instill LPS (5 mg/kg) to induce ALI. In some Notch1M-KO mice, endogenous macrophage Foxo1 was knocked down using a Foxo1 siRNA mix combined with mannose-conjugated polymers before the LPS challenge. Primary AEC IIs from WT mice were transfected with CRISPR/Cas9-mediated Jagged1 knockout (KO) or Jagged1 activation (ACT) vector, challenged with LPS (100 ng/mL), and cocultured with bone marrow-derived macrophages (BMMs). BMMs from Notch1M-KO mice were also obtained and transfected with CRISPR/Cas9-mediated Foxo1 knockout (KO) vector before subjected to LPS challenged. RESULTS:Herein, we discovered that recombinant Jagged1 administration in WT mice reduces LPS-induced ALI by promoting Notch signaling activation. Apoptotic AEC IIs release Jagged1, which activates Notch1 signaling in macrophages. Notably, myeloid-specific Notch1 deficiency exacerbates LPS-induced inflammation response and oxidative stress, accompanied by elevated Foxo1 and dysregulated TXNIP/NLRP3 activity. Mechanistically, Notch intracellular domain (NICD) and Foxo1 colocalized in the nucleus, where Foxo1 competed with NICD for RBP-Jκ binding, impairing Notch1 signaling and promoting inflammasome activation. Importantly, Foxo1 deletion in macrophages rescued these effects. CONCLUSIONS:Collectively, we characterized a novel molecular mechanism involving the Jagged1-Notch1-Foxo1 axis in regulating the TXNIP/NLRP3 pathway, which is dysregulated in ALI. These findings highlight the potential of targeting this pathway for therapeutic intervention in ALI.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease typically managed with broad-spectrum immunosuppressants that carry significant systemic side effects and often provide incomplete efficacy. While gut-microbiota-derived metabolites are known to influence AIH progression, the specific microbial drivers that maintain hepatic immune homeostasis remain poorly defined. Here, we show that Bacteroides acidifaciens (BA) and its metabolite 1-oleoyl-sn-glycero-3-phosphoethanolamine (O-LysoPE) are enriched in self-healing mouse models of hepatitis but markedly depleted in AIH patients. We demonstrate that O-LysoPE induces a 'hepatocyte-driven active immunosuppression' by targeting the Qa-1b (HLA-E): NKG2A immune checkpoint. Mechanistically, O-LysoPE selectively redirects the transcription factor Creb1 to the H2T23 promoter under inflammatory conditions, thereby upregulating hepatocytic Qa-1b expression. This elevation of Qa-1b engages the inhibitory receptor NKG2A on T cells, suppressing their overactivation and restoring a quiescent phenotype. Genetic disruption of H2T23 abrogates the hepatoprotective effects of O-LysoPE, confirming the central role of this metabolic-immune axis. Our findings reveal that the BA-O-LysoPE axis mobilizes the liver's intrinsic self-rescue mechanisms to restore immune quiescence. This study establishes a robust biological framework for liver-specific, targeted immunotherapy in AIH, offering a precision alternative to current systemic immunosuppression.

This study aimed to evaluate the diagnostic performance of ultrasound-derived fat fraction (UDFF) for metabolic dysfunction-associated steatotic liver disease (MASLD), by directly comparing it with the non-invasive gold standard MRI-PDFF and the established ultrasound method CAP. The diagnostic criteria for MASLD were used, we included 103 individuals with 53 MASLD patients and 49 healthy controls. All participants underwent liver MRI for MRI-PDFF quantification; ultrasound elastography for UDFF measurement; and vibration-controlled transient elastography for CAP assessment. Receiver operating characteristic (ROC) curves were generated to evaluate the performance of UDFF and CAP for predicting MRI-PDFF ≥ 5

Upper gastrointestinal bleeding (UGIB) is a prevalent and severe complication of cirrhosis, often resulting from esophagogastric variceal bleeding (EVB). This condition poses significant life-threatening risks. Once bleeding occurs, the risk of recurrent episodes substantially increases, further compromising liver function and worsening patient outcomes. This study aims to identify risk factors for UGIB in cirrhotic patients using clinical examination data and to develop a non-invasive predictive model to improve diagnostic precision and efficiency. Based on the inclusion and exclusion criteria, the study included 140 cirrhotic patients hospitalized at the First Affiliated Hospital of Nanjing Medical University between June 2022 and May 2023, who experienced UGIB within six months after discharge. These patients were compared with 151 cirrhotic patients hospitalized at the same hospital during the same period, who were discharged within six months without experiencing UGIB. General characteristics of the patients during hospitalisation, laboratory parameters on admission, and liver and spleen stiffness were retrospectively collected, and a retrospective case-control study was conducted. All patients were randomly assigned to the training and validation sets in a ratio of 7:3. Independent factors associated with UGIB were identified by univariate analysis, multivariate logistic regression analysis, and stepwise regression analysis, on the basis of which a predictive model was developed. The model’s performance was assessed via receiver operating characteristic (ROC) curve and decision curve analysis (DCA) and was compared with established prognostic models, including the Child-Pugh and MELD scores. The study analyzed 291 patients with cirrhosis, of whom 208 were allocated to the training set and 83 to the validation set. Independent predictors were identified, and predictive models were constructed using multivariate logistic regression analysis, and stepwise regression analysis in the training set, followed by validation in the validation set. The stepwise regression analysis identified ascites, spleen stiffness, albumin, fibrinogen, total cholesterol, and total bilirubin as independent predictors of UGIB (P < 0.05). These variables were incorporated into the predictive model. The area under the curve (AUC) for UGIB prediction was 0.956 in the training set and 0.909 in the validation set, demonstrating strong predictive performance. Furthermore, comparative analysis using ROC and DCA demonstrated that the developed model outperformed established scoring systems, such as the Child-Pugh score and the MELD score. Ascites, spleen stiffness, albumin, fibrinogen, total cholesterol and total bilirubin as independent predictors of UGIB in cirrhotic patients.

BACKGROUND AND AIM:The development of accurate noninvasive tests to identify individuals with metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis is of great clinical importance. In this study, we aimed to develop 2 noninvasive diagnostic models on the basis of routine clinical and laboratory data, using machine learning, to identify patients with MASH and significant fibrosis (fibrosis stages 2 to 4), respectively. METHODS:This analysis included the training (n=456) and the validation (n=105) sets of patients who underwent liver biopsy and laboratory testing for liver disease at 2 hospitals in China. Logistic regression, random forest, support vector machine, and the XGBoost algorithm were used to construct models, respectively. The best diagnostic models for MASH and significant fibrosis were compared with 7 existing noninvasive scoring systems including AAR, AST to platelet ratio index (APRI), BARD score, fibrosis-4 (FIB-4), fibrotic non-alcoholic steatohepatitis (NASH) index (FNI), homeostatic model assessment of insulin resistance (HOMA-IR), and non-alcoholic fatty liver disease fibrosis score (NFS). Performance was estimated by the area under the receiver operating characteristic curve (AUROC). RESULTS:The final noninvasive diagnostic model integrated 19 indicators derived from routine clinical and laboratory tests. The XGBoost models exhibited superior performance in MASH and significant fibrosis with an improved AUROC value (MASH, 0.670, 95% CI 0.530-0.811; significant fibrosis, 0.713, 95% CI 0.611-0.815) compared with other noninvasive scoring systems in the validation set. CONCLUSIONS:Utilizing machine learning can assist in diagnosing MASH and significant fibrosis based on clinical epidemiological information with good diagnostic performance.

High vitamin D concentrations may reduce the incidence of hepatocellular carcinoma (HCC), though results have been inconsistent. This study aimed to evaluate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and HCC, and to assess whether the genetic risk of HCC modifies this association. The prospective cohort study involved 447,028 individuals free of liver diseases in the UK Biobank. Serum 25(OH)D concentrations were measured by the chemiluminescent immunoassay method. The associations were evaluated using the Cox proportional hazards model, estimating hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Additionally, the weighted polygenic risk score (PRS) of HCC was calculated by 5 SNPs reported in a previously published genome-wide association study (GWAS). During a median follow-up of 12.5 years, 377 cases of HCC were documented. Compared to the lowest quartile of serum 25(OH)D, the HR (95% CI) of HCC was 0.52 (0.38-0.70) in the highest quartile. Per 10 nmol/L increase in serum 25(OH)D was associated with a 12% lower HCC risk (95% CI: 7%-17%). A joint effect of genetic and serum 25(OH)D on HCC risk was observed. Those with low genetic risk of HCC and the highest serum 25(OH)D had a HR (95% CI) of 0.22 (0.11-0.45) compared to those with high genetic risk of HCC and the lowest 25(OH)D serum levels, but there was no interaction (p interaction = 0.529). Our findings emphasize that higher serum 25(OH)D levels are linked to a reduced risk of HCC, indicating the potential role of 25(OH)D in the primary prevention of HCC.

Background: Notch1 signaling regulates innate immune-mediated inflammation in acute liver injury (ALI). However, the precise mechanism by which Notch1 governs macrophage polarization during ALI remains poorly understood. Methods: Wild-type (WT) mice received DAPT (10 mg/kg) prior to acetaminophen (APAP)-induced ALI. In parallel, bone marrow-derived macrophages (BMMs) were pretreated with either the β-catenin inhibitor XAV939 or the activator SKL2001, exposed to DAPT, and then challenged with lipopolysaccharide (LPS). Liver injury and inflammation were evaluated by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, immunofluorescence, quantitative real-time PCR (RT-PCR), and western blotting. Results: Unexpectedly, DAPT treatment exacerbated APAP-induced liver injury (AILI), resulting in more severe hepatocellular damage and inflammation than in controls. DAPT-treated macrophages exhibited enhanced pro-inflammatory cytokines expression and a shift toward an M1-like phenotype. Mechanistically, the β-catenin/glycogen synthase kinase 3 beta (GSK3β) signaling pathway emerged as a pivotal regulator of macrophage polarization. Conclusions: Notch1 inhibition unexpectedly worsens AILI by amplifying macrophage-driven pro-inflammatory responses via β-catenin signaling. These findings highlight the Notch1–β-catenin axis as a key regulator of hepatic macrophage function and a potential therapeutic target for sterile liver inflammation.

ABSTRACT Ultrasound‐derived fat fraction (UDFF) is designed to assess the hepatic fat content quantitatively. A multicenter study that verifies the diagnostic performance of UDFF for detecting hepatic steatosis has not yet been reported. This study aimed to evaluate the performance of UDFF for diagnosing and grading hepatic steatosis. Participants referred for assessment of hepatic steatosis were prospectively recruited from eight hospitals. All participants underwent UDFF and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) examinations. MRI‐PDFF was used as the reference for diagnosing hepatic steatosis. From January 2023 to July 2023, a total of 300 participants were included. The median body mass index was 25.4 kg/m2 (interquartile range: 22.7–28.1). UDFF values were positively correlated with MRI‐PDFF (R = 0.80, p < 0.001). Using MRI‐PDFF ≥ 5%, ≥ 15%, and ≥ 25% as the reference standard for detecting mild, moderate, and severe hepatic steatosis, the best cutoff values of UDFF were 7.6% (area under the receiver operating characteristic curves [AUC] = 0.90), 15.9% (AUC = 0.90), and 22.3% (AUC = 0.91), respectively. Thus, UDFF has excellent diagnostic performance in detecting and grading hepatic steatosis.

Dishevelled 2 (Dvl2) is a key mediator of the Wingless/Wnt signaling pathway that regulates cell proliferation, migration, and immune function. However, little is known about the role of macrophage Dvl2 in modulating NOD1-mediated pyroptosis and hepatocyte death in oxidative stress-induced inflammatory liver injury. In a mouse model of oxidative stress-induced liver inflammation, mice with myeloid-specific Dvl2 knockout (Dvl2M-KO) displayed exacerbated ischemia/reperfusion (IR) stress-induced hepatocellular damage with increased serum ALT levels, oxidative stress, and proinflammatory mediators. Unlike in Dvl2FL/FL controls, Dvl2M-KO enhanced NOD1, caspase-1, GSDMD, and NF-κB activation in liver macrophages after IR. Interestingly, IR stress enhanced YAP colocalized with HSF1 in Dvl2FL/FL macrophages, while macrophage Dvl2 deficiency reduced YAP and HSF1 colocalization in the nucleus under inflammatory conditions. Importantly, Dvl2 deletion diminished nuclear YAP interacted with HSF1 and augmented NOD1/caspase-1 and GSDMD activation in response to inflammatory stimulation. However, Dvl2 activation increased YAP interaction with HSF1 and activated HSF1 target gene eEF2, inhibiting NOD1/caspase-1, GSDMD, and NF-κB activity. Moreover, macrophage eEF2 deletion increased the NOD1-caspase-1 interaction, GSDMD activation, HMGB1 release, and hepatocyte LDH release after macrophage/hepatocyte co-culture. Adoptive transfer of eEF2-expressing macrophages in Dvl2M-KO mice alleviated IR-triggered liver inflammation and hepatocellular damage. Therefore, macrophage Dvl2 deficiency promotes NOD1-mediated pyroptosis and exacerbates IR-induced hepatocellular death by disrupting the YAP-HSF1 axis. eEF2 is crucial for modulating NOD1-driven pyroptosis, inflammatory response, and hepatocyte death. Our findings underscore a novel role of macrophage Dvl2 in modulating liver inflammatory injury and imply the therapeutic potential in organ IRI and transplant recipients.

Abstract Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH.

Background Liver stiffness measurement (LSM) via vibration-controlled transient elastography accurately assesses fibrosis. We aimed to develop a universal risk score for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. Methods We systematically selected predictors and developed the risk prediction model (HCC-LSM) in the hepatitis B virus (HBV) training cohort (n = 2251, median follow-up of 3.2 years). The HCC-LSM model was validated in an independent HBV validation cohort (n = 1191, median follow-up of 5.7 years) and a non-viral chronic liver disease (CLD) extrapolation cohort (n = 1189, median follow-up of 3.3 years). An HCC risk score was then constructed based on a nomogram. An online risk evaluation tool Liver Elastography-Based Hepatocellular Carcinoma Risk Score (LEBER) was developed using ChatGPT4.0. Results Eight routinely available predictors were identified, with LSM levels showing a significant dose-response relationship with HCC incidence (P < .001 by log-rank test). The HCC-LSM model exhibited excellent predictive performance in the HBV training cohort (C-index = 0.866) and the HBV validation cohort (C-index = 0.852), with good performance in the extrapolation CLD cohort (C-index = 0.769). The model demonstrated significantly superior discrimination compared to 6 previous models across the 3 cohorts. Cut-off values of 87.2 and 121.1 for the HCC-LSM score categorized participants into low-, medium-, and high-risk groups. An online public risk evaluation tool (LEBER; http://ccra.njmu.edu.cn/LEBER669.html) was developed to facilitate the use of HCC-LSM. Conclusion The accessible, reliable risk score based on LSM accurately predicted HCC development in patients with chronic hepatitis, providing an effective risk assessment tool for HCC surveillance strategies.

Background and Aims:Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA are structural somatic variants that indicate clonal hematopoiesis. This study aimed to investigate whether mCAs contribute to the risk of cirrhosis and modify the effect of a polygenic risk score (PRS) on cirrhosis risk prediction. Methods:mCA call sets of individuals with European ancestry were obtained from the UK Biobank. The PRS was constructed based on 12 susceptible single-nucleotide polymorphisms for cirrhosis. Cox proportional hazard models were applied to evaluate the associations between mCAs and cirrhosis risk. Results:Among 448,645 individuals with a median follow-up of 12.5 years, we identified 2,681 cases of cirrhosis, 1,775 cases of compensated cirrhosis, and 1,706 cases of decompensated cirrhosis. Compared to non-carriers, individuals with copy-neutral loss of heterozygosity mCAs had a significantly increased risk of cirrhosis (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.81). This risk was higher in patients with expanded cell fractions of mCAs (cell fractions ≥10% vs. cell fractions <10%), especially for the risk of decompensated cirrhosis (HR 2.03 [95% CI 1.09-3.78] vs. 1.14 [0.80-1.64]). In comparison to non-carriers of mCAs with low genetic risk, individuals with expanded copy-neutral loss of heterozygosity and high genetic risk showed the highest cirrhosis risk (HR 5.39 [95% CI 2.41-12.07]). Conclusions:The presence of mCAs is associated with increased susceptibility to cirrhosis risk and could be combined with PRS for personalized cirrhosis risk stratification.

Cholestatic liver disease, caused by the accumulation of hazardous bile acids in the liver, may result in cirrhosis, fibrosis, or liver failure. Activation of sirtuin 6(SIRT6) prevents cholestasis-associated pathological events, such as oxidative stress and mitochondrial biogenesis dysfunction, and inhibits bile acid synthesis to alleviate cholestatic liver injury. However, it remains uncertain which pathway mediates the therapeutic effect of SIRT6 in reducing cholestasis. Therefore, we treated liver-specific Sirt6 knockout mice with N-acetylcysteine,KEAP1-NRF2-IN-1, or acadesine to alleviate oxidative stress and/or promote mitochondrial biogenesis after modeling cholestatic liver disease, but these measures did not significantly improve cholestatic symptoms.However, MDL801, a SIRT6 agonist that downregulates cholesterol 7α-hydroxylase(CYP7A1, the key enzyme in bile acid synthesis) levels, exhibited favorable therapeutic effects. Additionally, the hepatic knockdown of Cyp7a1 further demonstrated that inhibiting hepatic bile acid synthesis might be the main pathway through which SIRT6 alleviates cholestatic liver disease. These findings provide a solid basis for the potential application of SIRT6 agonists in treating cholestatic liver disease.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a common chronic liver disease worldwide. No effective pharmacologic therapies for MASH have been developed; to develop such promising drugs, the underlying mechanisms regulating MASH need to be elucidated. Here, we aimed to determine the role of ovarian tumor domaincontaining protein 5 (OTUD5) in MASH progression and identify a specific mechanism. METHODS: The expression levels of OTUD subfamily under palmitic acid/oleic acid (PAOA) stimulation were screened. OTUD5 expression was assessed in human liver tissues withoutsteatosis, those with simple steatosis, and those with MASH. MASH models were developed in hepatocyte-specific Otud5- knockout mice that were fed high -fat high -cholesterol and highfat high -cholesterol plus high-fructose/sucrose diet for 16 weeks. RESULTS: The expression of OTUD5 was down -regulated in fatty liver and was negatively related to the progression of MASH. Lipid accumulation and inflammation were exacerbated by Otud5 knockdown but attenuated by Otud5 overexpression under PAOA treatment. Hepatocyte-specific Otud5 deletion markedly exacerbated steatosis, inflammation, and fibrosis in the livers of 2 MASH mouse models. We identified voltagedependent anion channel 2 (VDAC2) as an OTUD5-interacting partner; OTUD5 cleaved the K48 -linked polyubiquitin chains from VDAC2, and it inhibited subsequent proteasomal degradation. The anabolic effects of OTUD5 knockdown on PAOAinduced lipid accumulation were effectively reversed by VDAC2 overexpression in primary hepatocytes. Metabolomic results revealed that VDAC2 is required for OTUD5-mediated protection against hepatic steatosis by maintaining mitochondrial function. CONCLUSIONS: OTUD5 may ameliorate MASH progression via VDAC2-maintained mitochondrial homeostasis. Targeting OTUD5 may be a viable MASH -treatment strategy. (Cell Mol Gastroenterol Hepatol 2024;17:399-421; https://doi.org/ 10.1016/j.jcmgh.2023.11.014)