Journal of Hepatology最新文献

{"title":"Genetic and non-genetic drivers of histological progression and regression in MASLD","authors":"Eduardo Vilar-Gomez , Katherine P. Yates , David E. Kleiner , Cynthia Behling , Oscar W. Cummings , Laura A. Wilson , Tiebing Liang , Chaowapong Jarasvaraparn , Rohit Loomba , Jeffrey B. Schwimmer , Arun J. Sanyal , Jay Hoofnagle , Naga Chalasani","doi":"10.1016/j.jhep.2025.09.013","DOIUrl":"10.1016/j.jhep.2025.09.013","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The association between genetic variants and longitudinal changes in liver histology has not been well characterized. We examined relationships between three single nucleotide polymorphisms (SNPs) – <em>PNPLA3</em> rs738409<em>, TM6SF2</em> rs58542926, and <em>HSD17B13</em> rs72613567 – and longitudinal changes in liver histology.</div></div><div><h3>Methods</h3><div>A total of 671 (444 adults and 227 children) individuals enrolled in different NASH CRN studies and randomized controlled trials, with ≥2 serial liver biopsies, were analyzed. The main outcomes were progression from metabolic dysfunction-associated steatotic liver (MASL) to steatohepatitis (MASH), ≥1 stage increase in fibrosis, and resolution of MASH or fibrosis regression ≥1 stage. Interval-censored Cox models, adjusted for race/ethnicity, sex, age, BMI, type 2 diabetes mellitus (T2DM), and study cluster, were used to examine the associations between genetic variants and histological outcomes.</div></div><div><h3>Results</h3><div>The <em>PNPLA3</em> G allele increased the risk of fibrosis progression (adjusted hazard ratio [aHR] 1.31, 95% CI 1.05-1.64). The <em>HSD17B13</em> A allele attenuated MASL to MASH progression (aHR 0.46, 95% CI 1.5-3.9) and fibrosis progression (aHR 0.69, 95% CI 0.51-0.92) while increasing the likelihood of MASH resolution (aHR 1.58, 95% CI 1.13-2.22) and fibrosis regression (aHR 1.42, 95% CI 1.09-1.85). The <em>TM6SF2</em> T allele did not influence histological changes. An unweighted 3-SNP polygenic risk score, incorporating <em>PNPLA3</em>, <em>HSD17B13</em>, and <em>TM6SF2</em> risk alleles, was associated with an increased risk of MASL to MASH progression (aHR 1.33, 95% CI 1.03-1.71) and fibrosis progression (aHR 1.37, 95% CI 1.18-1.60). The unweighted sum of the 3-SNP non-risk alleles was associated with a higher chance of MASH resolution (aHR 1.21, 95% CI 1.02-1.43). Non-genetic factors, including T2DM and BMI change, also independently influenced histology. The effects of single variants and the PRS were significantly modified by age, sex, BMI, and T2DM.</div></div><div><h3>Conclusion</h3><div>Genetic predisposition and its significant interactions with non-genetic factors drive the dynamic trajectory of MASLD, providing a critical framework for personalized risk stratification and management.</div></div><div><h3>Impact and implications</h3><div>Histological changes in metabolic dysfunction-associated steatotic liver disease are driven by complex interactions between genetic and non-genetic factors, not by isolated influences. The <em>PNPLA3</em> rs738409 allele worsened fibrosis and steatosis, while the <em>HSD17B13</em> rs72613567 allele acted as a protective factor against progression and promoted regression. A polygenic risk score (PRS), based on three single nucleotide polymorphisms, comprising the sum of the three risk alleles, independently predicted histological progression. Conversely, the PRS of the ","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 502-516"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127773","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":"Tobevibart and elebsiran for the treatment of chronic hepatitis delta","authors":"Lisa Sandmann","doi":"10.1016/j.jhep.2025.12.018","DOIUrl":"10.1016/j.jhep.2025.12.018","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 677-678"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000613","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":"Strategies to address non-proportional hazards between survival curves - Lessons from phase III trials in hepatocellular carcinoma","authors":"Ezequiel Mauro , Tiago de Castro , Marcus Zeitlhoefler , Allan Hackshaw , MinJae Lee , Tim Meyer , Amit G. Singal , Josep M. Llovet","doi":"10.1016/j.jhep.2025.08.042","DOIUrl":"10.1016/j.jhep.2025.08.042","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Non-proportional hazards (NPH) can lead to discrepancies between interim (IA) and final analyses (FA) in randomized controlled trials (RCTs) of hepatocellular carcinoma (HCC). We assessed the impact of NPH in pivotal HCC trials and proposed strategies for more robust analyses.</div></div><div><h3>Methods</h3><div>Phase III pivotal HCC RCTs (2008–2024) were reviewed. Proportional hazards were tested using the Grambsch-Therneau method. For trials with NPH, we proposed an optimal IA timing (twice the estimated median of the primary endpoint in the control arm) or a minimum event threshold (≥60%). In NPH scenarios, the MaxCombo test, restricted mean survival time (rRMST), and piecewise hazard ratios were applied.</div></div><div><h3>Results</h3><div>NPH was present in 4/20 (20%) phase III trials in HCC, all involving immunotherapies, and displayed three patterns: 1) diminishing effects, 2) delayed effects, and 3) crossing hazards. Two RCTs (IMbrave050, LEAP-012) reported positive IA results with diminishing effects. In IMbrave050, discrepancies were observed when comparing IA and FA using MaxCombo analysis (<em>p =</em> 0.02 and <em>p =</em> 0.33, respectively), rRMST at 12 and 36 months (1.11 [<em>p</em> <0.001] and 1.08 [<em>p =</em> 0.08], respectively) and piecewise hazard ratios before <em>vs.</em> after 12 months (0.59 [95% CI 0.43-0.73] <em>vs.</em> 1.12 [95% CI 0.88-1.37]). In LEAP-012, results were consistent across 12 and 24 months (MaxCombo test <em>p <</em>0.001) and rRMST (1.20 [<em>p <</em>0.001) and 1.27 [<em>p <</em>0.001]). HIMALAYA and Checkmate 9DW reported positive results, which were confirmed by MaxCombo test. HIMALAYA showed delayed effects (rRMST at 12 and 36 months: 1.04 [<em>p =</em> 0.13] and 1.15 [<em>p =</em> 0.004]), while CheckMate 9DW displayed crossing hazards (rRMST at 12 and 36 months: 0.95 [<em>p =</em> 0.07] and 1.12 [<em>p =</em> 0.03]).</div></div><div><h3>Conclusion</h3><div>NPH contributed to discrepancies between IA and FA in IMbrave050. Robust IA require a minimum follow-up duration or event count before prematurely stopping RCTs in the presence of NPH.</div></div><div><h3>Impact and implications</h3><div>Non-proportional hazards (NPH) impact phase III randomized controlled trials in hepatocellular carcinoma, particularly in immunotherapy trials, potentially causing discrepancies between the interim and final analyses. In fact, halting trials at the interim analysis can be premature when NPH is present. Thus, we propose a framework to ensure study maturity based on follow-up duration and event accruals to optimize interim analyses in the presence of NPH. Whenever NPH is identified, distinct statistical tools should be used to assess reliable differences between arms (MaxCombo) and to assess the effect size (restricted mean survival time and piecewise hazard ratios) for regulatory decisions and clinical guidance. Implementing these strategies can improve tri","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 567-577"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116486","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":"PARG inhibition halts cholangiocarcinoma progression via the Hippo pathway and enhances response to chemotherapy and immunotherapy","authors":"Mincheng Yu ,&nbsp;Peiyi Xie ,&nbsp;Qiang Yu ,&nbsp;Yufei Zhao ,&nbsp;Wenxin Xu ,&nbsp;Zhangfu Yang ,&nbsp;Yujuan Wei ,&nbsp;Binghai Zhou ,&nbsp;Shuang Liu ,&nbsp;Sanyuan Dong ,&nbsp;Yongfeng Xu ,&nbsp;Yongsheng Xiao ,&nbsp;Bo Zhang ,&nbsp;Lei Guo ,&nbsp;Hui Li ,&nbsp;Qinghai Ye","doi":"10.1016/j.jhep.2025.09.018","DOIUrl":"10.1016/j.jhep.2025.09.018","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cholangiocarcinoma (CCA) is a lethal malignancy with limited therapeutic options. We investigated the oncogenic role of poly(ADP-ribose) glycohydrolase (PARG) and evaluated potential therapeutic strategies.</div></div><div><h3>Methods</h3><div>A tissue microarray comprising 275 CCA patient samples was analyzed by immunohistochemistry. Liquid chromatography–tandem mass spectrometry was utilized to identify downstream targets of PARG. Transgenic mice (<em>Parg</em>^<em>f/f</em>) were employed to establish a spontaneous CCA model via hydrodynamic tail vein injection and biliary instillation. The efficacy of PARG inhibition was assessed in multiple preclinical models, including patient-derived organoids, patient-derived xenografts, orthotopic xenografts, and an immunocompetent syngeneic murine model. Cytometry by time-of-flight analysis was used to profile changes in the tumor microenvironment following PARG inhibition and anti-PD-1 therapy.</div></div><div><h3>Results</h3><div>PARG was highly expressed in CCA and predicted a dismal prognosis based on analysis of a large patient cohort. Genetic depletion of <em>Parg</em> in spontaneous CCA models induced by two methods, including hydrodynamic tail vein injection and biliary instillation, significantly halted carcinogenesis. PARG inhibition alone showed impressive efficacy and potentiated that of gemcitabine/cisplatin in patient-derived organoid, patient-derived xenograft, and orthotopic models. Mechanistically, PARG dePARylates ITCH, suppressing its autoubiquitination and thereby inhibiting the Hippo pathway, which promotes CCA proliferation and chemoresistance. Moreover, cytometry by time-of-flight analysis revealed crosstalk between the tumor and stroma, which could be suppressed by PARG inhibitors via the TEADs/CXCR4/CXCL12 axis. Combining PD-1 blockade and gemcitabine/cisplatin with PARG inhibitors resulted in a significantly greater reduction in tumor burden, as well as a survival benefit.</div></div><div><h3>Conclusions</h3><div>Targeting PARG limits CCA progression, alleviates desmoplasia, and enhances response to both anti-PD-1 therapy and chemotherapy.</div></div><div><h3>Impact and implications</h3><div>Little is known about the role of PARG in cholangiocarcinoma (CCA) development and progression. Herein, we show that PARG expression is upregulated and hyperactivated in CCA, promoting tumor cell proliferation, cancer-associated fibroblast recruitment, and resistance to therapy. Pharmacological inhibition of PARG suppresses CCA development and could be an effective therapeutic strategy when combined with chemotherapy and immunotherapy.</div></div>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 599-617"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183266","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":"HBx-induced HSPB1 is a potential therapeutic target owing to its modulation of HBV cccDNA and hepatic immune responses","authors":"Hongfeng Yuan ,&nbsp;Lina Zhao ,&nbsp;Guang Yang ,&nbsp;Shuai Zhang ,&nbsp;Pan Lv ,&nbsp;Shuqin Zhang ,&nbsp;Yufei Wang ,&nbsp;Qiaomei Cai ,&nbsp;Changliang Shan ,&nbsp;Yunxia Liu ,&nbsp;Yu Geng ,&nbsp;Huihui Zhang ,&nbsp;Xiuzhu Gao ,&nbsp;Xiaomei Wang ,&nbsp;Zhenchuan Miao ,&nbsp;Ming Yin ,&nbsp;Man Zhao ,&nbsp;Junqi Niu ,&nbsp;Xishan Hao ,&nbsp;Xiaodong Zhang","doi":"10.1016/j.jhep.2025.09.033","DOIUrl":"10.1016/j.jhep.2025.09.033","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Chronic infection with HBV remains a significant public health concern, and current therapies are inadequate. Here, we report that HBx-elevated heat shock protein B1 (HSPB1) contributes to the regulation of HBV covalently closed circular DNA (cccDNA) and hepatic immune responses.</div></div><div><h3>Methods</h3><div>Molecular and cellular <em>in vitro</em> assays were employed to investigate the effects and underlying mechanisms of HSPB1 on HBV cccDNA and HBV replication in HBV-infected cells. The antiviral efficacy of candidate agents targeting cccDNA and the immune response was assessed in HBV-infected cells, human liver chimeric mice, and hydrodynamic injection-based HBV-persistent immunocompetent C57BL/6 mice.</div></div><div><h3>Results</h3><div>HSPB1 enhanced cccDNA stability by reducing the recruitment and binding of APOBEC3A/APOBEC3B to cccDNA. Interaction with HBx increased cellular HSPB1 levels by decreasing its ubiquitination, while enhanced phosphorylation promoted nuclear accumulation of HSPB1. Therapeutically, we developed a peptide, D-TK, derived from the HBXIP peptide sequence that targets HBx and limits cccDNA by blocking the interaction between HSPB1 and HBx, ultimately resulting in reduced HBV replication. Nobly, D-TK reduced the frequency of regulatory T cells and enhanced the frequency and activity of CD8⁺ T cells through HSPB1, thereby contributing to suppression of HBV replication.</div></div><div><h3>Conclusions</h3><div>HSPB1 represents a novel therapeutic target by modulating HBV cccDNA and immune responses in the liver. By suppressing cccDNA and enhancing immune responses, D-TK represents a promising therapeutic candidate for HBV treatment.</div></div><div><h3>Impact and implications</h3><div>Chronic infection with HBV remains a significant global health concern, and current therapeutic options are inadequate. In this study, we demonstrate that HBV X protein (HBx)-induced elevation of HSPB1 contributes to the regulation of HBV covalently closed circular DNA (cccDNA) and hepatic immune responses. We engineered a peptide, D-TK, that targets HBx, effectively suppresses cccDNA, and activates immune responses through HSPB1. Our findings offer new insights into the mechanism by which HBx-induced HSPB1 modulates HBV cccDNA and immune regulation in the liver.</div></div>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 517-530"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306134","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":"RePARylating biliary tumours to improve the efficacy of chemoimmunotherapy","authors":"Pedro M. Rodrigues ,&nbsp;Jesus M. Banales","doi":"10.1016/j.jhep.2025.10.028","DOIUrl":"10.1016/j.jhep.2025.10.028","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 496-498"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455468","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":"Enhancing intestinal goblet cell-associated antigen passages could attenuate ALD","authors":"Prakash Ramachandran","doi":"10.1016/j.jhep.2025.12.009","DOIUrl":"10.1016/j.jhep.2025.12.009","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 675-676"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948852","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":"Beyond relative thresholds: Towards actionable interventions for alcohol-attributable liver mortality","authors":"Kangkang Ji","doi":"10.1016/j.jhep.2025.09.008","DOIUrl":"10.1016/j.jhep.2025.09.008","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Page e95"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078531","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":"What’s next after the 2026 BCLC update?","authors":"Landon L. Chan,&nbsp;Stephen L. Chan","doi":"10.1016/j.jhep.2025.12.013","DOIUrl":"10.1016/j.jhep.2025.12.013","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 499-501"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784542","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":"From the Editor’s Desk...","authors":"Philip N. Newsome,&nbsp;Frank Tacke,&nbsp;Heiner Wedemeyer,&nbsp;Lorenza Rimassa,&nbsp;Annalisa Berzigotti,&nbsp;Tom H. Karlsen,&nbsp;Vlad Ratziu","doi":"10.1016/j.jhep.2026.01.005","DOIUrl":"10.1016/j.jhep.2026.01.005","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"84 3","pages":"Pages 479-482"},"PeriodicalIF":33.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205607","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}