Hepatology最新文献

{"title":"Multiomics combined with machine learning defines unique molecular subtypes of cholangiocarcinoma and identifies TNK1 as a therapeutic target.","authors":"Dong-Gi Mun,Erik Jessen,Jennifer L Tomlinson,Danielle Carlson,Rohit Budhraja,Roberto Alva-Ruiz,Amro Abdelrahman,Ryan Watkins,Lindsey Gregory,Chantal McCabe,Chen Wang,Rondell P Graham,Kathryn Woods,Martin Golkowski,Marshall Baker,Gregory J Gores,Sumera I Ilyas,Caitlin Conboy,Ellen L Larson,Jack W Sample,Enis H Ozmert,Richard K Kandasamy,Mitesh J Borad,Lewis Roberts,Joshua Andersen,Akhilesh Pandey,Rory L Smoot","doi":"10.1097/hep.0000000000001535","DOIUrl":"https://doi.org/10.1097/hep.0000000000001535","url":null,"abstract":"BACKGROUND AND AIMSCholangiocarcinoma (CCA) is one of the most lethal cancers, characterized by molecular heterogeneity and treatment resistance. To uncover new biological signals and therapeutic opportunities, we employed multiomic characterization combined with machine learning.APPROACH AND RESULTSWe profiled all anatomical CCA subtypes using whole exome sequencing, mRNA sequencing, and proteome/phosphoproteome analysis. Integrative dimensional reduction revealed RNA, protein, and phosphoprotein features driving tumor heterogeneity, enabling clustering. Machine learning algorithms identified molecular features for each cluster and mapped external datasets and patient-derived xenograft (PDX) models onto these clusters. Kinase enrichment analysis highlighted targetable kinases active in each cluster. In vivo validation was performed in cluster-specific PDX models using the selective TNK1 inhibitor, TP-5801. We identified three molecular clusters with distinct pathway characterization: immunomodulatory (cluster 1), metabolic (cluster 2), and gene regulation/cellular fate (cluster 3). Cluster assignment was independent of anatomic subtype but correlated with overall survival following curative-intent resection. We also identified multiomic features and pathways linked to overall survival and lymph node metastases, crucial for patient treatment selection. Kinase enrichment analysis pinpointed TNK1 as a highly active kinase in the metabolic cluster. Treatment with TP-5801 significantly reduced tumor growth in a metabolic PDX model, but not in models representing the other clusters. Combining internal data with publicly available datasets, we identified the immunomodulatory cluster as most responsive to gemcitabine/cisplatin therapy, confirmed in vivo using cluster-specific PDX models.CONCLUSIONSIntegrated multiomic characterization provides translational insights by defining unique molecular subtypes associated both with therapeutic response and overall clinical outcomes. This approach identified TNK1 as a previously unrecognized therapeutic target in a defined subset of CCA tumors.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"67 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182844","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":"Global Hepatitis C elimination: Updates, challenges, and opportunities from real-world experiences in Europe and North America.","authors":"Oana Săndulescu,Susanne Gjeruldsen Dudman,Ivana Gmizic,Federico Garcia,Heli Harvala,Imran Hasanoglu,Naveed Z Janjua,Justyna Kowalska,Vincent Mallet,Mojca Maticic,Mario U Mondelli,Eline L M Op de Coul,Ponni V Perumalswami,Gülşen Özkaya Şahin,Zeinab Said,Juan Francisco Sánchez-Avila,Petar Velikov,Nina Weis,Snjezana Zidovec-Lepej,Harrys A Torres, ","doi":"10.1097/hep.0000000000001548","DOIUrl":"https://doi.org/10.1097/hep.0000000000001548","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"41 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140316","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: Key advance in noninvasive fibrosis assessment: Evidence from China","authors":"Yongquan Chi, Wenzhu Li, Jianhua Rao","doi":"10.1097/hep.0000000000001546","DOIUrl":"https://doi.org/10.1097/hep.0000000000001546","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"10 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133659","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":"FXR splicing by SF3B3 promotes MYC-driven hepatocarcinogenesis.","authors":"Xue Wang,Jiahua Luo,Lifeng Han,Tong Xu,Haichuan Wang,Mingzhe Zhang,Gen Li,Xichuan Li,Weihua Zhang,Youcai Zhang","doi":"10.1097/hep.0000000000001523","DOIUrl":"https://doi.org/10.1097/hep.0000000000001523","url":null,"abstract":"BACKGROUND AND AIMSDysregulation of the MYC oncogene is a major genetic event in hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), a bile acid (BA) receptor, has emerged as a promising therapeutic target for various liver diseases. Both BA composition and FXR isoforms have been shown to be significantly altered in human HCCs. This study aimed to investigate their potential roles in MYC-driven hepatocarcinogenesis.APPROACH AND RESULTSHCC was induced in mice by hydrodynamic injection with MYC and MCL1 oncogenes. UPLC-MS/MS analysis revealed elevated BA levels, particularly primary conjugated BAs, in both serum and livers of MYC-driven HCC mice. qPCR and western blot analyses demonstrated suppression of BSEP and dysregulation of FXR splicing in the livers of these mice. Using RNA antisense purification coupled with mass spectrometry (RAP-MS), the splicing factor SF3B3 was identified as a regulator of FXR splicing. Both in silico and in vitro studies confirmed that SF3B3 is a direct downstream target of MYC in mice and humans. Functionally, overexpression of Fxrα2 and Fxrα4 or deletion of Sf3b3 significantly impeded MYC-driven hepatocarcinogenesis in mice. Moreover, combination treatment with a SF3B inhibitor and an FXR agonist synergistically suppressed proliferation of HCC cells. Analysis of clinical HCC samples revealed a positive correlation between SF3B3 and the relative expression of FXRα2.CONCLUSIONSSF3B3 is a key downstream effector of MYC-driven hepatocarcinogenesis and a critical regulator of FXR splicing. Both SF3B3 and FXR represent druggable vulnerabilities in MYC-amplified HCC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"9 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126996","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":"'Point-of-Care Ultrasound (POCUS) guided volume management and the effect of cirrhotic cardiomyopathy on acute kidney injury outcomes in cirrhosis'.","authors":"Madhumita Premkumar,Kamal Kajal,Akash Roy,Manhal Izzy,Smita Divyaveer,Anand V Kulkarni,Florent Artru,Prerna Sharma,Anchal Sandhu,Bhupendra Sihag,Ajay Bahl,Arka De,Nipun Verma,Sunil Taneja,Ajay Kumar Duseja,Arnab Pal,Harish Bhujade,K Rajender Reddy","doi":"10.1097/hep.0000000000001524","DOIUrl":"https://doi.org/10.1097/hep.0000000000001524","url":null,"abstract":"BACKGROUND AIMSPoint-of-care ultrasound(POCUS) helps in assessing volume status and cirrhotic cardiomyopathy(CCM). We evaluated POCUS-guided volume management and explored clinical predictors, including CCM, of acute kidney injury(AKI) reversal and need for renal replacement therapy(RRT), and survival, in cirrhosis and AKI between January 2023 and November 2024. Exclusions were patients with structural cardiac disease, portopulmonary hypertension, acute variceal bleeding, and septic shock.METHODSPOCUS was performed at ICU admission(Timezero), 24h,48h,72h, and as needed to guide volume management, and determine inferior vena cava(IVC) indices and cardiac index. CCM was defined by ≥3 of 4 variables(septal e' velocity, E/e' integral, left atrial volume index, tricuspid regurgitant velocity); clinical data were collected.RESULTS372 patients with AKI [84.7% men, aged 50.3±12 years, MELD-Na 23.9±5.1]; 296(79.6%), 42(11.3%), and 34(9.1%) were classified as hypovolemic, euvolemic, and hypervolemic at Timezero. Following POCUS-guided volume management, 231(62%) had pre-renal AKI; 61(16.4%) hepatorenal syndrome(HRS-AKI); 25(6.7%) HRS-AKD; 32(8.6%) HRS-CKD, while 23(6.2%) had a multifactorial etiology. CCM was diagnosed in 34.7%; 32.9% of pre-renal AKI, 75.4% in HRS-AKI, and 28% in HRS-AKD(p<0.001). Higher MAP0h (aHR1.9, 95%CI:1.96-2, p=0.039) and cardiac index0h(aHR1.2,95%CI:1.1-1.3,p=0.005) predicted AKI reversal at Day-7;53/372(14.2%) underwent RRT. Pulmonary edema developed in 4.8% overall; in 5.4% with CCM. Overall mortality was 46(12.4%) and 107(28.8%) at 90-days and 1-year. CCM predicted mortality at 90-days(aHR 8.9,95%CI:3.9-20.4,p<0.001) and one year(aHR1.7,95%CI:1.2-2.5,p=0.007). Cardiac index (aHR0.6,95%CI:0.4-0.9,p=0.005), and septal e' velocity(aHR 0.5,95% CI:0.3-0.7,p=0.010) predicted need for RRT.CONCLUSIONSPOCUS facilitates volume management and AKI reversal in cirrhosis. CCM predicts poor outcomes in HRS-AKI, need for RRT, and mortality.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"3 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127000","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: Key advance in noninvasive fibrosis assessment: Evidence from China.","authors":"Shenglong Li,Longfei You","doi":"10.1097/hep.0000000000001544","DOIUrl":"https://doi.org/10.1097/hep.0000000000001544","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"10 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126997","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":"Evolving Precision: Updates in Targeted Therapy for Cholangiocarcinoma","authors":"Giulia Tesini, Halima Ibrahim, Lorenza Rimassa, Chiara Braconi","doi":"10.1097/hep.0000000000001541","DOIUrl":"https://doi.org/10.1097/hep.0000000000001541","url":null,"abstract":"The development of Next Generation Sequencing (NGS) techniques for extended genomic profiling has led to the identification of actionable molecular alterations in approximately half of the patients with biliary tract cancer (BTC), with the highest incidences among those with intrahepatic cholangiocarcinoma. Targeted drugs have demonstrated to confer clinical benefit while maintaining a manageable safety profile. As a result, despite the lack of a head-to-head comparison with standard second line chemotherapy, they are now recommended for patients with advanced disease who are still fit after progression to first line palliative systemic anti-cancer treatment. In this review, we will contextualize the results observed with targeted drugs in clinical trials within the framework of clinical practice. We will provide an overview of available single-gene analyses that should be considered in case of lack of access to NGS, defining testing priorities, differences in yields, and therapeutic implications. Lastly, we will discuss future perspectives in the field of precision medicine for BTC, focusing on new strategies to overcome treatment resistance, on the optimal collocation of targeted drugs in the treatment algorithm, and on newly identified actionable alterations for which compounds are currently under investigation.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"59 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116487","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":"Erratum: Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC","authors":"Yujia Xia, Yu Wang, Qi Xiong, Jiayi He, Han Wang, Mozaffarul Islam, Xinyu Zhou, Alex Kim, Hongji Zhang, Hai Huang, Allan Tsung","doi":"10.1097/hep.0000000000001503","DOIUrl":"https://doi.org/10.1097/hep.0000000000001503","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"190 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116488","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":"Bile acid signaling in MASLD: from pathogenesis to therapeutic applications","authors":"Benedikt Simbrunner, Rafael Paternostro, Thomas Reiberger, Michael Trauner","doi":"10.1097/hep.0000000000001539","DOIUrl":"https://doi.org/10.1097/hep.0000000000001539","url":null,"abstract":"The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) causes considerable global morbidity and mortality. Dysregulated lipid and glucose metabolism are central elements in the pathogenesis of MASLD by promoting hepatocellular stress, inflammation, and liver fibrosis that may culminate in the development of cirrhosis and liver cancer. Moreover, intestinal dysbiosis and bacterial translocation trigger hepatic and systemic inflammation, further contributing to the pathogenesis and progression of MASLD. Bile acid (BA) receptors regulate hepatic metabolism and gut integrity as central players in the pathophysiology of MASLD. Therapeutic strategies targeting these BA receptors along the gut-liver axis, either directly through agonists or indirectly via modulation of BA transport, are currently within the focus of clinical research. This review summarizes mechanistic aspects of BA signaling in MASLD, key evidence of experimental and clinical studies on BA receptor agonists and provides an outlook for future opportunities and challenges on the road to the implementation of novel therapies targeting BA receptors and BA signaling in MASLD.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"28 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089723","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":"A targeted liver cancer therapy independent of immune checkpoint block","authors":"Bangyan L. Stiles","doi":"10.1097/hep.0000000000001543","DOIUrl":"https://doi.org/10.1097/hep.0000000000001543","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"4 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089722","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}