Hepatology最新文献

{"title":"Serum amyloid A1-Induced intrahepatic regulatory T cell dysfunction drives autoimmune hepatitis progression","authors":"Han Wang, Shuhui Wang, Yu Lei, Yu Chen, Zheng Huang, Shangshu Nie, Ping Han, Yujia Xia, Xinxia Feng, Jianyu Yu, Hao Li, Claire Chenwen Zhong, Wei Yan, Hai Huang, Dean Tian, Mei Liu","doi":"10.1097/hep.0000000000001419","DOIUrl":"https://doi.org/10.1097/hep.0000000000001419","url":null,"abstract":"Background & Aims: Treatment of autoimmune hepatitis (AIH) remains challenging and primarily relies on corticosteroid therapy. Regulatory T cells (Tregs), essential for maintaining immune homeostasis and preventing various autoimmune diseases, present a potential therapeutic target for AIH. However, the role of Tregs in AIH pathogenesis remains unclear. Approach & Results: In a well-established AIH model induced by hydrodynamic transfection of cytochrome P450 2D6 (CYP2D6) plasmid into mouse liver, Tregs were found to increase in number as the disease progressed. Despite the increased hepatic Treg presence, the proportions of effector T cells also rose, contributing to disease progression. Systemic Treg depletion using FoxP3-DTR/eGFP mice exacerbated AIH progression, while adoptive Treg transfer failed to alleviate liver inflammation and fibrosis, highlighting intrahepatic Treg dysfunction. Single-cell RNA sequencing of hepatic Tregs using the 10× Genomics platform identified impaired suppressive function and a shift toward pro-inflammatory phenotypes, contrasting with enhanced suppressive capacity observed in peripheral Tregs. This intrahepatic Treg dysfunction was associated with elevated hepatic serum amyloid A1 (SAA1) levels, which impaired Tregs via toll-like receptor 2 (TLR2). Liver-specific AAV8-mediated shSAA1 therapy restored Treg function and ameliorated AIH symptoms, while adoptive transfer of Tregs lacking TLR2 significantly improved disease outcomes. Conclusions: Intrahepatic Tregs exhibit a diminished suppressive phenotype and an enhanced effector phenotype, failing to control the escalating inflammation in AIH. AIH treatment should not only focus on increasing Treg number but also on restoring their functional capacity.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"80 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor microenvironment heterogeneity and progression mechanisms in intrahepatic cholangiocarcinoma: A study based on single-cell and spatial transcriptomic sequencing","authors":"Fengwei Li, Yao Li, Lishan Wang, Lei Xu, Hui Xue, Wenxin Wei, Yong Xia, Lei Wang, Feng Shen, Kui Wang","doi":"10.1097/hep.0000000000001423","DOIUrl":"https://doi.org/10.1097/hep.0000000000001423","url":null,"abstract":"Background and Aims: Intrahepatic cholangiocarcinoma (ICC) is characterized by high malignancy, and its global incidence is predicted to continue to increase over the past decades. However, the mechanisms underlying ICC pathogenesis and progression remain unclear. Approach and Results: The training cohort consisted of single-cell sequencing of 12 treatment-naïve ICC samples and spatial transcriptomics of four ICC samples. The validation cohort comprised of RNA-seq data from 87 ICC tumor samples. Finally, we validated our findings <jats:italic toggle=\"yes\">via</jats:italic> multiplex immunofluorescence, organoids, and mice models both <jats:italic toggle=\"yes\">in vivo</jats:italic> and <jats:italic toggle=\"yes\">in vitro</jats:italic>. We found significant heterogeneity within the tumor microenvironment (TME) of ICC patients. ICC cells were classified into five molecular subtypes, and we revealed that aspartate beta-hydroxylase (ASPH) was a marker gene for invasion subtypes. We then selected cepharanthine (CEP) as an ASPH inhibitor that effectively suppressed tumor progression. Regarding the ICC lymphatic metastasis mechanism, we found that tumor cells in N1 lymph nodes highly expressed tumor-specific MHC-II molecules but lacked co-stimulatory factors CD80/CD86, inducing a state of anergy in CD4+ T cells, which might facilitate ICC immune evasion. Conclusions: The TME of ICC was heterogeneous. ASPH markedly enhanced ICC invasion The ASPH inhibitor CEP significantly inhibits ICC progression and may serve as a targeted therapeutic drug for ICC. Tumor cells in N1 lymph nodes demonstrate high expression of tumor-specific MHC-II molecules, but silencing of co-stimulatory factors such as CD80/CD86 induces CD4+ T cells into an anergic state. Our study indicated that ASPH and MHC-II may serve as novel therapeutic targets for ICC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"10 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roadmap for a generally accepted model to predict first hepatic decompensation in compensated advanced chronic liver disease","authors":"Mattias Mandorfer, Mathias Jachs, Georg Semmler","doi":"10.1097/hep.0000000000001431","DOIUrl":"https://doi.org/10.1097/hep.0000000000001431","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"2 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arid1a deficiency promotes hepatocyte hyperpolyploidy and drives intrahepatic cholangiocarcinoma in mice","authors":"Qi Bian, Shu Wang, Zimin Song, Fang Liu, Muqing Cao, Nan Yang, Jun Ying, Jia-Syuan Hu, Xinyuan Xiong, Huiqin Zhu, Jun Wu, Jie Yang, Xiaonan Wang, Shunli Shen, Xuxu Sun","doi":"10.1097/hep.0000000000001422","DOIUrl":"https://doi.org/10.1097/hep.0000000000001422","url":null,"abstract":"Background &amp; Aims: Intrahepatic cholangiocarcinomas (ICCs) are aggressive liver tumors with high heterogeneity and limited therapeutic options. Although traditionally thought to arise from biliary cells, recent findings suggest that hepatocytes may also serve as a cellular origin for ICC. However, the mechanisms underlying hepatocyte malignant transformation and ICC initiation remain poorly understood. Approach and Results: We employed oncogene-driven and chemically induced ICC murine models, along with cellular models, to recapitulate the transformation of hepatocytes into ICC. Our findings demonstrate that mature hepatocytes undergo a significant hyperpolyploid state during ICC initiation. Hyperpolyploidy promotes aberrant cell division and chromosomal instability, accelerating hepatocyte transformation and ICC onset. Furthermore, we identified the chromatin remodeling factor <jats:italic toggle=\"yes\">Arid1a</jats:italic> as a critical suppressor of hyperpolyploidy. <jats:italic toggle=\"yes\">Arid1a</jats:italic> deficiency disrupts mitotic machinery at the centrosome, driving hyperpolyploidization and ICC tumorigenesis. Conclusions: Hepatocytes can transform into ICC through a process involving hyperpolyploidizaiton. This study offers new insights into the pathogenesis of ICC, particularly in patients harboring frequent <jats:italic toggle=\"yes\">ARID1A</jats:italic> mutations.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"11 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social determinants of health influence the risk of cirrhosis: A diverse nationwide cohort study","authors":"Dhiraj K. Peddu, Nicholas Tedesco, Stephanie M. Rutledge, Karn Wijarnpreecha, Ponni V. Perumalswami, Vincent L. Chen","doi":"10.1097/hep.0000000000001420","DOIUrl":"https://doi.org/10.1097/hep.0000000000001420","url":null,"abstract":"Background and Aims: Cirrhosis is a leading cause of mortality in the United States, with significant disparities influenced by social determinants of health (SDOH). This study evaluated the effects of SDOH on the risk of cirrhosis in a nationwide cohort of patients. Approach and Results: We conducted a retrospective cross-sectional cohort study from the All of Us Research Program (AOURP) enrolled 2017-2022. The primary outcome was cirrhosis, defined using International Classification of Disease codes. The primary predictors were SDOH factors measured by validated questionnaires and scaled to a 1-5 score or dichotomized. 83,061 adults with SDOH assessments were included in the final cohort, of whom 1,008 had cirrhosis. Neighborhood-level factors of social disorder (per-point OR 1.36, 95% CI 1.21-1.54, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001) and crime (per-point OR 1.17, 95% CI 1.10-1.24, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001) were linked to increased cirrhosis risk. Combined neighborhood and individual-level factors of food insecurity (OR 2.00, 95% CI 1.71-2.32, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001) and everyday discrimination (per-point OR 1.19, 95% CI 1.09-1.30, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001) were similarly associated with higher risk. Conversely, social cohesion (per-point OR 0.83, 95% CI 0.76-0.90, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001), English proficiency (OR 0.64, 95% CI 0.49-0.84, <jats:italic toggle=\"yes\">p</jats:italic>=0.001), and social support (per-point OR 0.82, 95% CI 0.78-0.87, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001) were associated with decreased risk of cirrhosis. The population attributable fraction for most SDOH ranged from 0.10 to 0.15. Conclusions: SDOH factors were strongly associated with the risk of cirrhosis in a diverse nationwide population and explained a high proportion of variability in cirrhosis risk. SDOH should be considered key modifiable risk factors for advanced liver disease.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"6 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor: Mitigating missing data bias and confounding on large-scale cohort studies of metabolic syndrome-cholangiocarcinoma associations","authors":"Bokang Yan, Weiwei Lai, Zuli Wang","doi":"10.1097/hep.0000000000001418","DOIUrl":"https://doi.org/10.1097/hep.0000000000001418","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"31 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor: Liver stiffness progression comparison between diabetics and non-diabetics with biopsy-proven metabolic dysfunction-associated steatosis","authors":"Zhongbao Zuo, Chunli Yang, Miaochan Wang, Jing Wu, Aifang Xu","doi":"10.1097/hep.0000000000001414","DOIUrl":"https://doi.org/10.1097/hep.0000000000001414","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MASTL/YBX1/PAK4 axis regulated by stress-activated STK24 triggers lenvatinib resistance and tumor progression in hepatocellular carcinoma","authors":"Bu-Gang Liang, Yi-Min Zheng, Ming-Hao Xu, Chao Gao, Wen-Xin Xu, Jun-Bo Chen, Si-Wei Wang, Guo-Huan Yang, Long-Tao Zhao, Li Yuan, A-Ying Ma, Ze-Ning Dong, Jia-Bin Cai, Hui-Chuan Sun, Ai-Wu Ke, Ying-Hao Shen","doi":"10.1097/hep.0000000000001392","DOIUrl":"https://doi.org/10.1097/hep.0000000000001392","url":null,"abstract":"Background and Aims: Many patients with hepatocellular carcinoma (HCC) present inadequate responses to lenvatinib therapy. Therefore, it is important to elucidate the underlying mechanisms of resistance and to formulate effective reversal strategies. Methods: We conducted comprehensive transcriptome and proteome sequencing analyses of lenvatinib-resistant cell lines and patient tissues to identify critical genes and proteins associated with lenvatinib resistance. Subcutaneous mouse models were established, the half maximal inhibitory concentration (IC<jats:sub>50</jats:sub>) was determined, and colony formation assays were employed to investigate the biological role of microtubule-associated serine/threonine kinase-like (MASTL) in tumor progression and therapeutic resistance. Molecular and biochemical methodologies, including RNA sequencing, chromatin immunoprecipitation sequencing, and mass spectrometry, were employed to explore the underlying mechanisms by which MASTL contributes to poor responses to lenvatinib in HCC. Results: MASTL was frequently upregulated in lenvatinib-resistant HCC cells and tissues. Increased expression of MASTL drove lenvatinib resistance through reactivation of mitogen-activated protein kinase (MAPK) signaling pathways, which is typically inhibited by lenvatinib. Mechanistically, MASTL directly phosphorylated Y-box binding protein-1 (YBX1) at S102, thereby facilitating its transcriptional activation of p21-activated kinase 4 (PAK4). PAK4 subsequently activated MEK1/2, thereby promoting lenvatinib resistance. Additionally, the findings revealed that STK24, a stress-regulated kinase, can activate MASTL under lenvatinib exposure. Notably, disrupting the MASTL/YBX1/PAK4 axis restored sensitivity to lenvatinib. Conclusion: We propose that the MASTL/YBX1/PAK4 axis, which is activated by stress-induced STK24, plays a crucial role in lenvatinib tolerance. Inhibiting this axis by targeting MASTL effectively overcomes lenvatinib resistance in HCC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"117 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144202066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: Liver transplantation for primary and secondary liver tumours-Patient-level meta-analyses compared to UNOS conventional indications.","authors":"Ruben Ciria, Daniel Aliseda, Giammauro Berardi, Fernando Rotellar, Gonzalo Sapisochin","doi":"10.1097/HEP.0000000000001272","DOIUrl":"10.1097/HEP.0000000000001272","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E173-E174"},"PeriodicalIF":12.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mendelian randomization in hepatology: A review of principles, opportunities, and challenges.","authors":"Yilin Song, Ting Ye, Lewis R Roberts, Nicholas B Larson, Stacey J Winham","doi":"10.1097/HEP.0000000000000649","DOIUrl":"10.1097/HEP.0000000000000649","url":null,"abstract":"<p><p>Mendelian randomization has become a popular tool to assess causal relationships using existing observational data. While randomized controlled trials are considered the gold standard for establishing causality between exposures and outcomes, it is not always feasible to conduct a trial. Mendelian randomization is a causal inference method that uses observational data to infer causal relationships by using genetic variation as a surrogate for the exposure of interest. Publications using the approach have increased dramatically in recent years, including in the field of hepatology. In this concise review, we describe the concepts, assumptions, and interpretation of Mendelian randomization as related to studies in hepatology. We focus on the strengths and weaknesses of the approach for a non-statistical audience, using an illustrative example to assess the causal relationship between body mass index and NAFLD.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1836-1846"},"PeriodicalIF":12.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49687376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}