Journal of Clinical and Translational Hepatology最新文献

{"title":"Assessment of Metabolic Dysfunction-associated Steatotic Liver Disease and Liver Fibrosis: A Cross-sectional Study in Asymptomatic Individuals in Greater Vancouver.","authors":"Nicholas W Tjandra, David M P Di Fonzo, Tianyi Wen, Kirby Lau, Peter Kwan, Eric M Yoshida, Daljeet Chahal","doi":"10.14218/JCTH.2025.00109","DOIUrl":"10.14218/JCTH.2025.00109","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatic fibrosis, yet its prevalence in asymptomatic populations remains unclear. This study aimed to assess the prevalence of steatosis and significant fibrosis in asymptomatic individuals without known liver disease in the Greater Vancouver Area.</p><p><strong>Methods: </strong>Interested individuals voluntarily registered online via the Canadian Liver Foundation website or by telephone. Inclusion criteria included age ≥ 19 years, no known liver disease, and low alcohol intake (<30 g/day for men, <20 g/day for women). Demographic and clinical data were collected, and all participants underwent transient elastography after a 3-h fast. The study aimed to collect 4,500 analyzable scans while reflecting the region's ethnic diversity.</p><p><strong>Results: </strong>A total of 4,193 participants were analyzed. The median age was 62 years, the median body mass index was 25.4, and 45% were male. Asian individuals comprised 42% of the cohort. Steatosis was present in 59.6% of participants, and 45.7% met diagnostic criteria for MASLD. Significant fibrosis (F2-F4) was found in 8.6%. Age, male sex, ethnicity, cardiac disease, diabetes, hypertension, and obesity were significantly associated with fibrosis. Logistic regression analysis confirmed age, weight, diabetes, dyslipidemia, hypertension, and obesity as independent predictors.</p><p><strong>Conclusions: </strong>A substantial proportion of asymptomatic individuals in Greater Vancouver have undetected MASLD and significant fibrosis. Early identification of high-risk groups may support broader implementation of transient elastography screening. This study provides one of the first North American population-based estimates of MASLD and fibrosis stratified by ethnicity, offering new insights into liver disease distribution among Caucasian, Chinese, and South Asian populations.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"535-541"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCNE1 Promotes the Progression of Hepatic Precancerous Lesion and the Malignant Phenotype of Hepatocellular Carcinoma.","authors":"Kai Zhang, Xue Hu, Lichao Yao, Wenzhi Guo","doi":"10.14218/JCTH.2024.00428","DOIUrl":"10.14218/JCTH.2024.00428","url":null,"abstract":"<p><strong>Background and aims: </strong>The diagnosis of hepatic precancerous lesions (HPC) and early hepatocellular carcinoma (HCC) has significant public health implications and holds the potential to reduce the global burden of HCC. This study aimed to identify molecular features and biomarkers associated with HPC progression and early HCC development.</p><p><strong>Methods: </strong>RNA sequencing was used to identify differentially expressed genes in mouse HPC tissues and normal liver tissues. Cyclin E1 (CCNE1) expression in HPC tissues and HCC cells was assessed using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. The effects of CCNE1 on HCC cell proliferation, migration, invasion, and apoptosis were evaluated using colony formation, wound healing, Transwell assays, and flow cytometry. The mechanism of CCNE1 was explored through Kyoto Encyclopedia of Genes and Genomes pathway analysis and gene set enrichment analysis and further validated through <i>in vitro</i> experiments. The interaction between CCNE1 and tumor-associated macrophages (TAMs) was investigated by co-culturing HCC cells with macrophages.</p><p><strong>Results: </strong>RNA sequencing and TCGA database analysis showed that CCNE1 expression was significantly elevated in mouse HPC tissues and human HCC samples and was associated with reduced survival rates. <i>In vitro</i> assays demonstrated that CCNE1 promoted HCC cell proliferation, migration, invasion, and survival by activating the PI3K/Akt signaling pathway. Additionally, CCNE1 induced TAM polarization toward the M2 phenotype by promoting the expression of CCL2 and CCL5 in HCC cells.</p><p><strong>Conclusions: </strong>CCNE1 promotes HPC progression and HCC cell proliferation, migration, invasion, and survival by activating the PI3K/Akt signaling pathway. Furthermore, CCNE1 enhances the secretion of CCL2 and CCL5 by HCC cells, promoting TAM infiltration and M2 polarization, thereby contributing to tumor progression.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"555-567"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Gut Microbiota in Elderly Patients with Acute Hepatitis E Infection.","authors":"Miaomiao Li, Meng Shi, Changyi Ji, Luyu Wang, Ze Xiang, Ying Wang, Hongtao Wang, Mengmeng Gu, Runing Ji, Jian Wu","doi":"10.14218/JCTH.2025.00111","DOIUrl":"10.14218/JCTH.2025.00111","url":null,"abstract":"<p><strong>Background and aims: </strong>Gut dysbiosis has been reported in severe liver diseases. However, information on the impact of hepatitis E virus infection on the gut microbiota, and the association between enteric microbiota disturbances and acute hepatitis E (AHE), is limited, particularly in elderly patients with AHE (AHE-elderly). Our objective was to characterize the AHE-specific microbiome in elderly patients and evaluate its association with clinical outcomes.</p><p><strong>Methods: </strong>Fecal samples and clinical data were collected from 58 AHE-elderly patients (46 self-healing cases, 12 non-self-healing cases) and 30 elderly patients with healthy controls (hereinafter referred to as HCs-elderly). Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Bioinformatic analyses, including alpha diversity and STAMP, were performed. The predictive potential of <i>Bacteroides fragilis</i> was assessed using statistical analysis and receiver operating characteristic curves.</p><p><strong>Results: </strong>Alpha diversity indices showed no significant differences in microbial diversity between the AHE-elderly and HCs-elderly groups, nor between self-healing and non-self-healing groups among AHE-elderly patients. Nevertheless, a trend toward altered species richness was observed. In the AHE-elderly group, the relative abundance of <i>Firmicutes</i>, <i>Lactobacillales</i>, and <i>Bacilli</i> increased significantly. Meanwhile, compared with the self-healing group, <i>Bacteroidetes</i> were more abundant in the non-self-healing group. At the species level, <i>Bacteroides fragilis</i> was the most abundant in the non-self-healing group, significantly contributing to the divergence in gut microbiota between the two groups.</p><p><strong>Conclusions: </strong>The relative abundance of <i>Bacteroidetes</i> significantly distinguished AHE-elderly patients from healthy controls and could more accurately predict recovery outcomes in elderly AHE patients. These findings suggest new strategies for preventing and managing AHE recurrence in the elderly patients.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"578-587"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics of a Chinese Cohort of Patients with Chronic Hepatitis C Infection (2019-2023) and a Case Report of Resistance-associated Substitutions to Sofosbuvir-velpatasvir Treatment.","authors":"Hao Xiong, Shaokun Pan, Chaohui Zhou, Hong Shi, Youhua Xie, Jinsheng Guo","doi":"10.14218/JCTH.2025.00033","DOIUrl":"10.14218/JCTH.2025.00033","url":null,"abstract":"","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"605-608"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term Physical Activity Reduces Metabolic-associated Steatohepatitis by Promoting the Degradation of Branched-chain Amino Acids in Skeletal Muscle.","authors":"Mingshu Gao, Jiaying Li, Yanan Zhang, Jiangtao Huang, Jiaqi Chen, Dawen Liao, Shengnan He, Qian Bi, Lele Ji, Yulu Du","doi":"10.14218/JCTH.2025.00072","DOIUrl":"10.14218/JCTH.2025.00072","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic-associated steatohepatitis (MASH) is an advanced and progressive liver disease that potentially causes cirrhosis and hepatocellular carcinoma. Exercise is a crucial and effective intervention for ameliorating metabolic dysfunction-associated steatotic liver disease. This study aimed to provide a comprehensive understanding of the underlying mechanisms of MASH, which benefit a broad spectrum of MASH patients, including those who have difficulty engaging in physical activity.</p><p><strong>Methods: </strong>We established a mouse model of MASH and selectively knocked down L-type amino acid transporter 1 and alanine-serine-cysteine transporter 2. Mice were fed a high-fat high-cholesterol diet and subjected to either short- or long-term exercise regimens. We assessed the phosphorylation and activity of branched-chain alpha-keto acid dehydrogenase (BCKDH) as well as branched-chain amino acid (BCAA) content in skeletal muscle following exercise.</p><p><strong>Results: </strong>Short-term exercise significantly reduced hepatic steatosis and inflammation without causing notable changes in body weight. It also enhanced BCKDH activity in skeletal muscle and decreased hepatic BCAA accumulation. Muscle-specific overexpression of BCKDH further promoted BCAA catabolism and significantly attenuated hepatic steatosis and inflammation in high-fat high-cholesterol-fed mice. In contrast, muscle-specific L-type amino acid transporter 1 knockdown, which suppresses BCAA uptake, markedly abolished these beneficial effects. Interestingly, BCKDH overexpression in muscle increased glutamine levels in both the blood and liver. Hepatic alanine-serine-cysteine transporter 2 knockdown, which inhibited glutamine uptake, lessened the protective effect of exercise on MASH. Further <i>in vitro</i> study revealed that glutamine derived from myocytes improved redox homeostasis and inhibited lipid accumulation in hepatocytes.</p><p><strong>Conclusions: </strong>Short-term exercise enhances BCAA catabolism in skeletal muscle and promotes glutamine production, which circulates to the liver to improve redox balance and alleviate MASH.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"542-554"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-mitochondrial Antibodies in Patients with Elevated Alkaline Phosphatase/Gamma-glutamyl Transferase Levels: Hallmark or Bystander?","authors":"Fukui Zhang","doi":"10.14218/JCTH.2025.00168","DOIUrl":"10.14218/JCTH.2025.00168","url":null,"abstract":"","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"533-534"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interim Analysis of 48-week Tenofovir Amibufenamide Treatment in Chronic Hepatitis B Patients with Normal Alanine Aminotransferase Levels: The PROMOTE Study.","authors":"Honglian Gui, Yingqiu Shen, Lin Tan, Piao Hu, Feng Qian, Xiaoping Wu, Yuanwang Qiu, Sujun Zheng, Jiaojian Lv, Yunzhen Shi, Jun Li, Yongfang Jiang, Zhizhen Hu, Fanru Nie, Yan Huo, Lihong Qu, Qing Xie","doi":"10.14218/JCTH.2025.00162","DOIUrl":"10.14218/JCTH.2025.00162","url":null,"abstract":"<p><strong>Background and aims: </strong>Chronic hepatitis B virus (HBV)-infected patients may exhibit liver fibrosis and other pathological changes despite normal alanine aminotransferase (ALT). This study aimed to assess the efficacy and safety of tenofovir amibufenamide (TMF) in chronic HBV-infected patients with normal ALT levels.</p><p><strong>Methods: </strong>The ongoing PROMOTE study (NCT05797714) is the first prospective, multicenter, randomized, open-label, blank-controlled clinical trial involving chronic HBV-infected patients with normal ALT levels. Participants were randomized in a 1:1 ratio to receive either TMF (TMF group) or no treatment (blank control group). The primary efficacy endpoint was the proportion of participants achieving HBV DNA levels <20 IU/mL at 48 weeks.</p><p><strong>Results: </strong>A total of 197 participants were enrolled, with 95 in the TMF group and 102 in the blank control group. At 48 weeks, a significantly greater proportion of participants in the TMF group achieved HBV DNA levels <20 IU/mL compared with the control group (74.2% vs. 9.0%, <i>P</i> < 0.001). The TMF group demonstrated more pronounced reductions in HBV DNA (-2.63 vs. -0.22 log₁₀ IU/mL, <i>P</i> < 0.001), HBsAg (-0.07 vs. -0.04 log₁₀ IU/mL, <i>P</i> = 0.02), and ALT levels (-14.09% vs. 0%, <i>P</i> = 0.003) compared with the blank control. In the TMF group, the proportion of participants with high-normal ALT levels (20-40 IU/L) was reduced. No significant differences were observed between the groups in creatinine, glomerular filtration rate, bone turnover biomarkers, lipid profiles, or phosphorus levels.</p><p><strong>Conclusions: </strong>TMF treatment demonstrates significant efficacy in chronic HBV-infected patients with normal ALT levels and shows a favorable safety profile regarding bone, renal, and lipid parameters. The PROMOTE study is ongoing, and further results at 96 and 144 weeks are expected to provide additional insights.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 7","pages":"568-577"},"PeriodicalIF":4.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleanolic Acid Restores Drug Sensitivity in Sorafenib-resistant Hepatocellular Carcinoma: Evidence from <i>In Vitro</i> and <i>In Vivo</i> Studies.","authors":"Tongtong Li, Xuan Shen, Tao Zhang, Jiaheng Ren, Wang Wang, Didi Wang, Pengxia Zhang","doi":"10.14218/JCTH.2024.00369","DOIUrl":"10.14218/JCTH.2024.00369","url":null,"abstract":"<p><strong>Background and aims: </strong>Hepatocellular carcinoma (HCC) remains challenging to treat in advanced stages, primarily due to the development of resistance to sorafenib. There is an urgent need for novel therapeutic strategies to overcome this resistance. This study aimed to investigate the potential of oleanolic acid (OA), a natural hepatoprotective compound, in mitigating sorafenib resistance and elucidate its underlying molecular mechanisms.</p><p><strong>Methods: </strong>Sorafenib-resistant Huh7 and HepG2 cell lines were established to mimic the resistant phenotype. The effects of OA on these cells were evaluated by assessing cell invasion, migration, and sensitivity to sorafenib. Gene expression analysis was conducted to identify molecular changes induced by OA treatment, with a focus on <i>fabp3</i> expression.</p><p><strong>Results: </strong>Oleanolic acid significantly inhibited the invasive and migratory capabilities of sorafenib-resistant Huh7 and HepG2 cells (<i>p</i> < 0.01). Furthermore, OA treatment downregulated <i>fabp3</i> expression and restored the cells' sensitivity to sorafenib.</p><p><strong>Conclusions: </strong>Oleanolic acid shows promise as an adjunct therapy for overcoming sorafenib resistance in HCC. By reducing cell aggressiveness and restoring drug sensitivity, OA may enhance the therapeutic efficacy of current treatments for advanced HCC.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"469-483"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Discrimination and Predictive Ability of Novel Prognostic Scores for Long-term Mortality in Hospitalized Patients with Cirrhosis.","authors":"Sipu Wang, Gaoyue Guo, Han Wang, Xuqian Zhang, Wanting Yang, Jie Yang, Liping Wu, Chao Sun","doi":"10.14218/JCTH.2025.00004","DOIUrl":"10.14218/JCTH.2025.00004","url":null,"abstract":"<p><strong>Background and aims: </strong>Since the adoption of novel prognostic scores, such as the iterative model for end-stage liver disease (MELD 3.0) and the gender-equity model for liver allocation (GEMA), their utility has markedly expanded to diverse clinical scenarios. However, data concerning their prognostic value in more generalized cirrhotic populations are scarce. In this study, we aimed to elucidate the MELD 3.0/GEMA-Na for long-term mortality risk stratification and refine their usage scope.</p><p><strong>Methods: </strong>This study retrospectively reviewed 310 hospitalized patients with decompensated cirrhosis. Discrimination and stratification were compared between MELD 3.0/GEMA-Na and other scores. Validation was performed in another 120 subjects.</p><p><strong>Results: </strong>In the investigated cohort, the median MELD-Na, MELD 3.0, and GEMA-Na were 9 (7, 12), 12 (10, 17), and 12 (9, 17), respectively. Compared to their predecessors, both MELD 3.0 and GEMA-Na models exhibited consistently better discriminative ability, especially in relation to long-term mortality. This effect was more pronounced for GEMA-Na, which was the only score to present an area under the receiver operating characteristic curve greater than 0.8 up to two years (0.807). Statistical analysis indicated that a MELD 3.0 score of 18 and a GEMA-Na score of 20 were the most optimal cutoffs to rank the risk of death, both of which were independently associated with two-year all-cause transplant-free mortality (MELD 3.0: hazard ratio: 1.13, 95% confidence interval: 1.10, 1.17; GEMA-Na: hazard ratio: 1.12, 95% confidence interval: 1.10, 1.17, both <i>P</i> < 0.001). Similar findings were affirmed in the validation cohort.</p><p><strong>Conclusions: </strong>MELD 3.0 is superior to other MELD-based scores for long-term prognostication in hospitalized patients with cirrhosis, while GEMA-Na demonstrated even better accuracy and performance.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"484-492"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal Depletion of TM6SF2 Exacerbates High-fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease through the Gut-liver Axis.","authors":"Li-Zhen Chen, Yu-Rong Wang, Zhen-Zhen Zhao, Shou-Lin Zhao, Cong-Cong Min, Yong-Ning Xin","doi":"10.14218/JCTH.2024.00407","DOIUrl":"10.14218/JCTH.2024.00407","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common form of chronic liver disease worldwide. This study aimed to explore the role of TM6SF2 in high-fat diet (HFD)-induced MASLD through the gut-liver axis.</p><p><strong>Methods: </strong>The TM6SF2 gut-specific knockout (TM6SF2 GKO) mouse was constructed using CRISPR/Cas9 technology. TM6SF2 GKO and wild-type (CON) mice were fed either a HFD or a control diet for 16 weeks to induce MASLD. Blood, liver, and intestinal lipid content, as well as gut microbiota and serum metabolites, were then analyzed.</p><p><strong>Results: </strong>TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice. The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice. The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase, alanineaminotransferase, and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice, while triglyceride levels were lower. Serum metabolite analysis revealed that HFD-fed TM6SF2 GKO mice had an increase in the expression of 17 metabolites (e.g., LPC [18:0/0-0]) and a decrease in 22 metabolites (e.g., benzene sulfate). The differential metabolites of LPC (18:0/0-0) may serve as HFD-fed TM6SF2 serum biomarkers, leading to MASLD exacerbation in GKO mice.</p><p><strong>Conclusions: </strong>TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice. TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"443-455"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}