Currently, no therapies are approved for alcohol-associated liver disease (ALD). Here, we identify cyclophilin D (CypD) as a critical mediator in the progression of ALD. We observe elevated expression of CypD in ALD patients and a corresponding mouse model. Hepatocyte-specific knockout of CypD mitigates hepatic mitochondrial dysfunction, steatosis, inflammation, and oxidative stress. Conversely, overexpression of CypD exacerbates hepatic mitochondrial stress. In vivo and in vitro experiments demonstrate that a CypD inhibitor, RN-0001, effectively and safely alleviates hepatic damage induced by ethanol exposure; these protective effects are absent in CypD-deficient mice. Biophysical assays indicate that RN-0001 directly binds to CypD. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) tests and first-in-human phase I clinical trial identify RN-0001 as a promising translational candidate for ALD therapy. Collectively, our study highlights the pathological role of CypD in ALD and introduces a preclinical candidate for its management. This study was registered at chictr.org.cn (ChiCTR2500106709).

While magnesium isoglycyrrhizinate (MgIG) is a clinically approved therapy for alcohol-associated liver disease (ALD), its precise molecular targets and mechanisms remain uncharacterized. This study aimed to define MgIG's hepatoprotective actions in chronic-binge ALD mouse models and ethanol/palmitic acid-exposed AML-12 hepatocytes. Through an integrated strategy encompassing RNA sequencing, molecular docking, and microscale thermophoresis, we discovered that MgIG directly binds to hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) at residue 187, a finding corroborated by molecular dynamics simulations. In vivo, MgIG markedly attenuated alcohol-induced liver injury, evidenced by ameliorated histological damage, reduced hepatic steatosis, and normalized liver-to-body weight ratios. In vitro, it effectively reduced lipid accumulation, inflammation, and apoptosis. Mechanistically, RNA sequencing identified isopentenyl diphosphate delta isomerase 1 (IDI1) as a key downstream effector. Hepatocyte-specific genetic manipulations confirmed that MgIG modulates the SREBP2-IDI1 axis, thereby suppressing lipogenesis, inflammatory responses, and apoptotic pathways. We reveal HSD11B1 as a novel direct molecular target of MgIG and elucidate its therapeutic mechanism through the HSD11B1-SREBP2-IDI1 signaling axis, which profoundly impacts ALD pathogenesis. These findings not only validate MgIG's clinical utility but also highlight a promising new therapeutic target for ALD.

Abstract Background Alcohol-associated liver disease (ALD) has emerged as a major cause of chronic liver disease and liver-related mortality in China. This study aimed to project the future burden of ALD in Chinese adults from 2020 to 2050, including prevalence of ALD, number of alcoholic steatohepatitis (ASH) cases, incident hepatocellular carcinoma (HCC) cases, liver transplantation (LT) demand, liver-related deaths, and disability-adjusted life years (DALYs). Methods We developed an agent-based state-transition microsimulation model with yearly cycles and a lifetime horizon. The model simulated 5,678,912 representative Chinese adults (mean age 36.2 years, 51.2% male). Health states included no steatosis, alcohol-associated steatotic liver, ASH, fibrosis stages F0-F4, decompensated cirrhosis, HCC, LT, and liver-related death. Model inputs were derived from the China Kadoorie Biobank, Global Burden of Disease Study 2021, China’s national surveys, published meta-analyses, and transplant registry data. Projections incorporated demographic shifts, alcohol consumption trends, and calibrated transition probabilities. Uncertainty was assessed via 1,000 Monte Carlo simulations generating 95% uncertainty intervals. Results ALD prevalence was projected to increase from 4.8% (55 million individuals) in 2020 to 8.5% (94 million individuals) by 2050. ASH cases rose from approximately 18 million to 20 million. Annual incident HCC cases nearly doubled from 20,500 in 2020-2025 to 45,200 by 2046-2050. LT demand quadrupled from 2,300 to 9,800 cases. Liver-related deaths increased from 50,000 in 2020 to 85,000 in 2050, while DALYs rose from 1.5 million to 2.6 million. Conclusions In the absence of strengthened alcohol control policies, ALD will impose a substantial and growing burden on China’s health system by 2050, with marked increases in HCC incidence, LT demand, and liver-related mortality.

Protein tyrosine phosphatase type IVA 3 (PTP4A3) is implicated in the metastasis of hepatocellular carcinoma (HCC), yet its precise regulatory mechanisms remain elusive. This study aimed to identify the interacting substrates and underlying mechanisms of PTP4A3 to inform the optimization of PTP4A3-targeted therapies in HCC. Using the TurboID system and protein mass spectrometry, over 500 candidate substrates for PTP4A3 were identified. A direct interaction between PTP4A3 and epidermal growth factor receptor (EGFR) was also validated. Ti-IMAC protein phosphorylation mass spectrometry revealed that PTP4A3 dephosphorylates Thr693 of EGFR. This dephosphorylation event enhanced EGFR-ERBB2 heterodimerization, leading to increased RhoA-GTPase activation, cell motility, and cytoskeletal rearrangement. EGFR/ERBB2 inhibition effectively suppressed PTP4A3-driven metastasis both in vitro and in vivo. This study reveals a novel mechanism by which PTP4A3 promotes HCC metastasis via direct dephosphorylation of EGFR at Thr693. Lapatinib, an inhibitor of EGFR/ERBB2, effectively suppressed PTP4A3-driven HCC metastasis, offering a potential therapeutic strategy for HCC patients with high PTP4A3 expression.The regulatory mechanism of PTP4A3 regulating HCC cell metastasis. PTP4A3 overexpression promotes EGFR-ERBB2 heterodimer formation by dephosphorylating EGFR at Thr693, inhibiting its degradation. This sustained EGFR activation enhances HCC cell motility via RhoA-GTP signaling. Lapatinib, an EGFR/ERBB2 inhibitor, effectively counteracts the pro-migratory effects of PTP4A3.

This review provides a critical examination of the sex-specific impact of alcohol consumption on the development and progression of hypertension. Specifically, it elucidates the differential roles of alcohol metabolism and blood pressure regulatory mechanisms in men and women. Finally, it explores promising sex-specific therapeutic strategies for the management of alcoholic hypertension. Emerging evidence indicates significant sex-based disparities in alcohol pharmacokinetics and pharmacodynamics, with women exhibiting heightened susceptibility to alcohol-induced cardiovascular sequelae. Crucially, key mechanistic insights reveal the differential modulation of the renin-angiotensin-aldosterone system (RAAS), oxidative stress pathways, and the intricate interplay of sex hormones, including the protective effects of estrogen and the potential pro-hypertensive effects of testosterone. Consequently, contemporary therapeutic avenues are increasingly focusing on targeting these sex-specific pathophysiological mechanisms. Alcoholic hypertension manifests with distinct sex-related etiologies and underlying mechanisms, necessitating the development of tailored therapeutic interventions. Effective management strategies should prioritize addressing sex-specific differences in oxidative stress, RAAS activation, and the implementation of personalized lifestyle modifications.

AIMS:The organ communication mechanisms driven by alcohol-associated liver disease (ALD) remain inadequately understood. This study explores the endocrine roles of the hepatokine angiotensinogen (AGT) and the renin-angiotensin system (RAS) in ALD. METHODS AND RESULTS:Hepatokine screening tests revealed that chronic-binge ethanol consumption upregulates hepatic AGT production, triggering downstream RAS activation. Hepatocyte-specific knockout of Agt (AGTΔHep) significantly alleviated ALD-induced liver injury. In organ screening between AGTflox/flox (AGTf/f) and AGTΔHep mice, skeletal muscle exhibited the most pronounced improvement in alcoholic myopathy (AM)-related phenotypes, including reduced muscle mass, enhanced oxidative stress, and mitochondrial dysfunction post-ethanol administration. Mechanistically, the renin-angiotensin axis transmits damaging signals from AGT to their membrane receptor AGTR1 in both hepatocytes and myocytes. Pharmacological inhibition of AGT, renin, and angiotensin-converting enzyme, as well as specific knockdown of Agtr1 in hepatocytes or myocytes, effectively attenuated both conditions. Activation of the counteractive axis of the RAS-AGTR1 pathway, involving Ang (1-7) and its membrane receptor MAS1, ameliorated the alcoholic injury of both the liver and muscle. Conversely, specific knockdown of Mas1 in hepatocytes and myocytes exacerbated these injuries. CONCLUSIONS:Our work demonstrates that hepatokine AGT promotes ALD and AM through the activation of the RAS-AGTR1 axis and the inhibition of the Ang(1-7)-MAS1 axis, offering a foundation for concurrent therapeutic strategies for both diseases.

Goji berry is a famous edible and medicinal substance around the world. In this research, 15 phenylpropionyl phenylethylamine derivatives(1-15), in cluding one new compound(1), were separated and identified from g oji berry. All isolates were elucidated via ex tensive nuclear magnetic resonance spectral analyses and chemical techniques. Six known isolates were first obtained from Lycium genus. Six isolates were effectively split in to double chromatographic peaks accompanied by the basically identical areas, indicating they belong to racemates. The oxygen radical absorbance capacity(ORAC) experiment indicated that all isolates displayed a capacity of scavenging free radicals, and most of them exhibited higher ORAC than epigallocatechingallate. In ethanol/palmitic acid-established in vitro hepatocyte injury model, four phenylpropionyl phenylethylamine derivatives(1, 2, 9, and 15) significantly alleviated hepatocyte injury, among which compound 1 exerted the strongest protective activity. Notably, the hepatoprotective effect of compound 1 was further confirmed in ethanol-established liver damage mouse model, reflected by the reduction of lipid accumulation and the attenuation of pathological alteration. Combined with the in vitro results, the in vivo observations suggested that compound 1 suppressed cell apoptosis and the outburst of inflammation. Our findings provided first-hand evidence proving that goji berry-derived phenylpropionyl phenylethylamine derivatives hold a potential in treating alcoholic liver disease.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

OBJECTIVE:This study aims to evaluate and summarize the current state of gender equality for female scientists in obesity research. METHODS:We conducted a comprehensive analysis of governmental funding, high-impact publications/citations, and awards received by female and male scientists engaged in obesity research worldwide. Median citations were compared by sex and year, with group differences assessed using the nonparametric Mann-Whitney U test. RESULTS:Our findings reveal a concerning difference: In most representative countries, a higher proportion of male principal investigators received grant support, with Japan exhibiting the most pronounced gender bias. In highly cited obesity papers, female corresponding authors constituted only 33%, with Japan having the lowest representation at a mere 5%, whereas the Netherlands approached near-equal representation (49%). Furthermore, highly cited obesity papers authored by women generally received fewer citations than those by men across most analyzed years and countries. However, a positive trend emerged in awards: the European Association for the Study of Obesity and the Association for the Study of Obesity recognized female scientists at a higher rate than male scientists. CONCLUSIONS:These findings highlight a complex landscape. Although female scientists have gained increased support and recognition in several countries, significant gender inequality persists in obesity research.

ObjectiveTo investigate the effects of the Mediterranean diet (MD) on hepatic metabolism and gut microbiota in mice with metabolic dysfunction-associated steatotic liver disease (MASLD).MethodsC57BL/6 mice were fed a high-fat diet for 12 weeks to induce MASLD, with normal chow (NC)-fed mice as controls. Post-modeling, MASLD mice were randomized into three groups: HF (continued high-fat diet), HF-NC (switched to normal chow), and HF-MD (switched to MD). After 18-week interventions, body/liver weights, serum liver enzymes (ALT, AST), hepatic glycolipid markers (glucose, TC, TG, IBIL, DBIL), inflammatory cytokines (IL-6, TNF-α; ELISA), and histopathology (H&E and Oil Red O staining) were analyzed. Gut microbiota (metagenomic sequencing) and short-chain fatty acids (SCFAs; targeted metabolomics) were profiled.ResultsHigh-fat diet induced MASLD features including obesity, increased abdominal fat mass, hepatic steatosis with lipid droplets, and inflammation. Both HF-NC and HF-MD groups exhibited reduced body weight, liver index, hepatic cytokines, serum enzymes, and improved glucolipid profiles vs. HF group (p < 0.05), with histopathology confirming attenuated steatosis. HF-MD outperformed HF-NC in lowering ALT, AST, IL-6, and TNF-α (p < 0.05). MASLD mice showed gut dysbiosis characterized by decreased diversity, elevated Alistipes, Helicobacter, Mucispirillum, and Chlamydia, reduced SCFAs, and increased branched-chain fatty acids (BCFAs) (p < 0.05). Both dietary interventions partially ameliorated gut dysbiosis in MASLD mice, with the HF-MD group uniquely enriching beneficial taxa including Prevotella, Muribaculum, Duncaniella, and Barnesiella.ConclusionMD alleviates MASLD progression by synergistically improving hepatic metabolic homeostasis and gut microbiota composition, demonstrating superior efficacy over NC in mitigating inflammation, enriching beneficial microbes, and regulating microbial metabolism. These findings highlight MD's potential as a targeted dietary intervention for MASLD.

The reversal of liver fibrosis requires effective strategies to reduce oxidative stress and inhibition of hepatic stellate cell (HSC) activation. MiR-4500 regulates pathological angiogenesis and collagen mRNA stability, with the potential to inhibit fibrosis. Herein, we explored the inhibition of HSC activation in vitro by exosomes (Exos) carrying miR-4500 and encapsulated ExosmiR-4500 in an intelligent injectable hydrogel with biological activity and reactive oxygen species (ROS) responsiveness for application in oxidative stress environments. Briefly, reversible boronic ester bonds were integrated into gelatin-based hydrogels through dynamic crosslinking of quaternized chitosan (QCS) and 4-carboxyphenylboronic acid (CPBA)-modified gelatin. The QCS-CPBA-Gelatin (QCG) hydrogel scavenged excess ROS from the local microenvironment and released ExosmiR-4500 through the dissociation of boronic ester bonds, providing a favorable microenvironment and in situ sustained-release drug delivery system for ExosmiR-4500. The results showed that QCG@ExosmiR-4500 hydrogel has biocompatibility, biodegradability, and slow-release ability, which could effectively clear ROS and inhibit HSC activation and pathological angiogenesis in vitro and in vivo. Furthermore, transcriptome analysis suggests that the pharmacological mechanism of the QCG@ExosmiR-4500 hydrogel is mainly related to anti-oxidation, anti-angiogenesis, anti-fibrosis processes, and signaling pathways. Thus, our study demonstrates that an intelligently responsive ExosmiR-4500 delivery system based on injectable hydrogels is a promising strategy for the treatment of liver fibrosis.

Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.

We assessed the global incidence, mortality, and disability-adjusted life years (DALYs) associated with various liver diseases, including alcohol-related liver disease (ALD), hepatitis B/C virus infections (HBV or HCV), liver cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), and other chronic liver diseases, from the 2019 Global Burden of Disease study. Additionally, we analyzed the global trends in hepatology research and drug development. From 2000 to 2019, prevalence rates increased for ALD, MASLD and other liver diseases, while they decreased for HBV, HCV, and liver cancer. Countries with a high socio-demographic index (SDI) exhibited the lowest mortality rates and DALYs. The burden of liver diseases varied due to factors like sex and region. In nine representative countries, MASLD, along with hepatobiliary cancer, showed highest increase in funding in hepatology research. Globally, the major research categories in hepatology papers from 2000 to 2019 were cancer, pathobiology, and MASLD. The United States (U.S.) was at the forefront of hepatology research, with China gradually increasing its influence over time. Hepatologists worldwide are increasingly focusing on studying the communication between the liver and other organs, while underestimating the research on ALD. Cancer, HCV, and MASLD were the primary diseases targeted for therapeutic development in clinical trials. However, the proportion of new drugs approved for the treatment of liver diseases was relatively low among all newly approved drugs in the U.S., China, Japan, and the European Union. Notably, there were no approved drug for the treatment of ALD in the world.

The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3−/− and Cxcl10−/−) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3−/− and Cxcl10−/− stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3−/−or Cxcl10−/− recipient mice (CD45.2) and examined donor-contributed hematopoiesis. Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10−/− stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10−/− donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.

Summary: Background: Liver disease is linked to series of extrahepatic multisystem manifestations. However, little is known about the associations between liver and eye diseases, especially cataract, the global leading cause of blindness. We aimed to investigate whether severe liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, and liver fibrosis and cirrhosis, were associated with an increased risk of the cataract. Methods: A total of 326,558 participants without cataract at baseline enrolled in the UK Biobank between 2006 and 2010 were included in this prospective study. The exposures of interest were severe liver diseases (defined as hospital admission), including NAFLD, ALD, viral hepatitis and liver fibrosis and cirrhosis. The outcome was incident cataract. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Each liver disease was first treated as a binary time-varying variable to investigate its association with cataract, and then was treated as a ternary time-varying variable to examine the recent (liver disease within 0–5 years) vs. long-term (liver disease > 5 years) state associations with the risk of cataract. Findings: After a median follow-up of 13.3 years (interquartile range, 12.5–14.0 years), 37,064 individuals were documented as developing cataract. Higher risk of cataract was found in those with severe NAFLD (HR, 1.47; 95% CI, 1.33–1.61), ALD (HR, 1.57; 95% CI, 1.28–1.94) and liver fibrosis and cirrhosis (HR, 1.58; 95% CI, 1.35–1.85), but not in individuals with viral hepatitis when exposure was treated as a binary time-varying variable (P = 0.13). When treating exposure as a ternary time-varying variable, an association between recently diagnosed viral hepatitis and cataract was also observed (HR, 1.55; 95% CI, 1.07–2.23). Results from the combined model suggested they were independent risk factors for incident cataract. No substantial changes were found in further sensitivity analyses. Interpretation: Severe liver diseases, including NAFLD, ALD, liver fibrosis and cirrhosis and recently diagnosed viral hepatitis, were associated with cataract. The revelation of liver-eye connection suggests the importance of ophthalmic care in the management of liver disease, and the intervention precedence of patients with liver disease in the early screening and diagnosis of cataract. Funding: National Natural Science Foundation of China, Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission, Clinical Research Plan of Shanghai Shenkang Hospital Development Center, Shanghai Municipal Key Clinical Specialty Program, the Guangdong Basic and Applied Basic Research Foundation and Shenzhen Science and Technology Program.

Intravenous thrombolysis (IVT) and dual antiplatelet therapy (DAPT) have been widely used in minor ischemic stroke (MIS) treatment. However, the clinical outcomes and safety of these two treatments have not been compared within the early thrombolytic time window. Here, we conducted a multicenter, ambispective cohort study involving patients with MIS presenting within 4.5 h of symptom onset at 3 affiliated hospitals of Jinan University from 2018–2022. The patients were divided into the IVT group and DAPT group. The primary outcome was a 90-day excellent outcome (mRS ≤ 1). A total of 1,026 patients were enrolled, of whom 492 were assigned to the IVT group and 534 were assigned to the DAPT group. The IVT group had better 90-day excellent outcomes (mRS ≤ 1) than the DAPT group (OR 1.69, 95

Gut microbiota is linked to human metabolic diseases. The previous work showed that leucine deprivation improved metabolic dysfunction, but whether leucine deprivation alters certain specific species of bacterium that brings these benefits remains unclear. Here, this work finds that leucine deprivation alters gut microbiota composition, which is sufficient and necessary for the metabolic improvements induced by leucine deprivation. Among all the affected bacteria, B. coccoides is markedly increased in the feces of leucine-deprived mice. Moreover, gavage with B. coccoides improves insulin sensitivity and reduces body fat in high-fat diet (HFD) mice, and singly colonization of B. coccoides increases insulin sensitivity in gnotobiotic mice. The effects of B. coccoides are mediated by metabolizing tryptophan into indole-3-acetic acid (I3AA) that activates the aryl hydrocarbon receptor (AhR) in the liver. Finally, this work reveals that reduced fecal B. coccoides and I3AA levels are associated with the clinical metabolic syndrome. These findings suggest that B. coccoides is a newly identified bacterium increased by leucine deprivation, which improves metabolic disorders via metabolizing tryptophan into I3AA.

Background Excessive alcohol intake with hepatitis B virus (HBV) infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease. Hepatitis B virus X protein (HBx) plays a crucial role in disease pathogenesis, while its specific role in alcoholic liver disease (ALD) progression has not yet been elucidated. Here, we studied the role of HBx on the development of ALD. Methods HBx-transgenic (HBx-Tg) mice and their wild-type littermates were exposed to chronic plus binge alcohol feeding. Primary hepatocytes, cell lines, and human samples were used to investigate the interaction between HBx and acetaldehyde dehydrogenase 2 (ALDH2). Lipid profiles in mouse livers and cells were assessed by using liquid chromatography-mass spectrometry. Results We identified that HBx significantly aggravated alcohol-induced steatohepatitis, oxidative stress, and lipid peroxidation in mice. In addition, HBx induced worse lipid profiles with high lysophospholipids generation in alcoholic steatohepatitis, as shown by using lipidomic analysis. Importantly, serum and liver acetaldehyde were markedly higher in alcohol-fed HBx-Tg mice. Acetaldehyde induced lysophospholipids generation through oxidative stress in hepatocytes. Mechanistically, HBx directly bound to mitochondrial ALDH2 to induce its ubiquitin-proteasome degradation, resulting in acetaldehyde accumulation. More importantly, we also identified that patients with HBV infection reduced ALDH2 protein levels in the liver. Conclusions Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.