Pub Date : 2026-02-11DOI: 10.1016/j.jhep.2026.01.022
Nina Desboeufs, Achim Weber
{"title":"Targeting the tumour's Achilles heel: ATR inhibition to exploit a constitutive vulnerability of hepatoblastoma","authors":"Nina Desboeufs, Achim Weber","doi":"10.1016/j.jhep.2026.01.022","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.01.022","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"6 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152736","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}
Pub Date : 2026-02-11DOI: 10.1016/j.jhep.2025.12.027
Florent Artru
{"title":"One year after the TransMet trial: Transplant oncology at a turning point","authors":"Florent Artru","doi":"10.1016/j.jhep.2025.12.027","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.12.027","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"394 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153307","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":"Landscape of ALF Neuroprotection Without Invasive Monitoring","authors":"Yajie Wang","doi":"10.1016/j.jhep.2026.02.005","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.02.005","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors' contributions</h2>Yajie Wang: Conceptualization, Project administration, Writing - original draft.</section></section><section><section><h2>Data availability statement (delete if not applicable)</h2>Not available.</section></section><section><section><h2>Financial support</h2>Not available.</section></section><section><section><h2>Conflict of interest</h2>This manuscript has no conflicts of interest.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"394 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153673","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}
Pub Date : 2026-02-10DOI: 10.1016/j.jhep.2026.01.021
Asier Rabasco Meneghetti, Claudia Campani, Charles Roux, Zunamys Itzel Carrero, Dan-Adrian Popica, Giuliana Amaddeo, Marie Lequoy, Clémence Hollande, Sarah Mouri, Mathilde Wagner, Vincent Plaforet, Sabrina Sidali, Maxime Ronot, Marika Rudler, Alain Luciani, Olivier Sutter, Eleonore Spitzer, Hélène Regnault, Sanaâ El Mouhadi, Violaine Ozenne, Nathalie Ganne-Carrié, Mohamed Bouattour, Jean Charles Nault, Dominique Thabut, Jakob Nikolas Kather, Manon Allaire
{"title":"Detection of Esophageal Varices and Prediction of Hepatic Decompensation in Unresectable Hepatocellular Carcinoma using AI","authors":"Asier Rabasco Meneghetti, Claudia Campani, Charles Roux, Zunamys Itzel Carrero, Dan-Adrian Popica, Giuliana Amaddeo, Marie Lequoy, Clémence Hollande, Sarah Mouri, Mathilde Wagner, Vincent Plaforet, Sabrina Sidali, Maxime Ronot, Marika Rudler, Alain Luciani, Olivier Sutter, Eleonore Spitzer, Hélène Regnault, Sanaâ El Mouhadi, Violaine Ozenne, Nathalie Ganne-Carrié, Mohamed Bouattour, Jean Charles Nault, Dominique Thabut, Jakob Nikolas Kather, Manon Allaire","doi":"10.1016/j.jhep.2026.01.021","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.01.021","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"211 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153309","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}
Pub Date : 2026-02-06DOI: 10.1016/j.jhep.2026.02.001
Sami F. Qadri, Kimmo Porthan, Sylvie Dufour, Tiina E. Lehtimäki, Kitt Falk Petersen, Gerald I. Shulman, Hannele Yki-Järvinen, Panu K. Luukkonen
Background & Aims
Weight loss is the cornerstone therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome compared with a non-ketogenic diet (ND).
Methods
Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare KD and ND effects on in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS evaluated systemic metabolic responses.
Results
Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (−29% vs. −20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (−54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (−34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and tricarboxylic acid cycle intermediates.
Conclusions
Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury.
Impact and Implications
This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in MASLD. The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD.
{"title":"Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD","authors":"Sami F. Qadri, Kimmo Porthan, Sylvie Dufour, Tiina E. Lehtimäki, Kitt Falk Petersen, Gerald I. Shulman, Hannele Yki-Järvinen, Panu K. Luukkonen","doi":"10.1016/j.jhep.2026.02.001","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.02.001","url":null,"abstract":"<h3>Background & Aims</h3>Weight loss is the cornerstone therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome compared with a non-ketogenic diet (ND).<h3>Methods</h3>Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare KD and ND effects on <em>in vivo</em> rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS evaluated systemic metabolic responses.<h3>Results</h3>Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (−29% <em>vs.</em> −20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% <em>vs.</em> 21%). KD, but not ND, markedly reduced serum insulin concentrations (−54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD<sup>+</sup>] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (−34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and tricarboxylic acid cycle intermediates.<h3>Conclusions</h3>Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury.<h3>Impact and Implications</h3>This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in MASLD. The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD.<h3>Clinical trial number</h3>NCT03737071","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"41 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134198","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}
Pub Date : 2026-02-06DOI: 10.1016/j.jhep.2026.01.015
Jean-Charles Nault, Claudia Campani, Theo Z. Hirsch, Ethan Neumann, Waqar Arif, Sandrine Imbeaud, Marina Baretti, Marianne Ziol, Sabrina Sidali, Pauline Roger, Manon Allaire, Mohamed Bouattour, Fabio Marra, Brice Fresneau, Neus Llarch, Jean-Marie Peron, René Gerolami, Eric Nguyen Khac, Pierre Nahon, Nathalie Ganne-Carrié, Jessica Zucman-Rossi
Introduction
Fibrolamellar carcinoma (FLC) is a rare primary liver cancer that predominantly affects young patients with normal known serum tumor biomarkers. An observation of an elevated procalcitonin (PCT) in one patient prompted us to investigate PCT as a biomarker in a larger cohort of FLC.
Methods
We measured serum PCT levels in 34 samples from 18 patients with FLC and in 64 patients with hepatocellular carcinoma (HCC), 24 with cholangiocarcinoma (CCA), and 20 with cirrhosis. Using RNA sequencing, we analyzed CALCA expression, encoding PCT, in 27 FLC tumors, 331 HCC tumors, 39 CCA tumors, 71 hepatoblastomas, 34 hepatocellular adenomas, and 55 non-tumor livers. Spatial transcriptomics was performed on three FLC and PCT immunohistochemistry on 13 FLC and 34 other primary or secondary liver cancers.
Results
In 8 FLC from the European cohort, median serum PCT was significantly elevated (55.2 μg/l) compared to patients with HCC (0.14 μg/l), CCA (0.16 μg/l), and cirrhosis (0.11 μg/l; P=0.0005). It was validated in a U.S. cohort of 10 FLC patients compared to HCC and CCA (P=0.0002). Across these cohorts, elevated serum PCT was observed in 83% of FLC cases versus 3% of HCC and CCA (P<0.0001). In four patients, changes in serum PCT levels correlated with radiologic response according to RECIST 1.1. RNA sequencing demonstrated significant overexpression of CALCA in FLC compared to other primary liver tumors (P<0.0001), and spatial transcriptomics localized CALCA expression specifically to tumor cells. Immunohistochemistry confirmed PCT overexpression in 77% of FLC but not in other liver cancers.
Conclusion
Procalcitonin is a sensitive and specific serum biomarker for FLC among primary liver cancers, with potential utility in diagnosis and monitoring of treatment response.
Impact and implications
This study is justified by the lack of reliable serum biomarkers for fibrolamellar carcinoma and demonstrates that procalcitonin is specifically overexpressed by FLC tumor cells and detectable in the blood of the patients with FLC. These findings are important for clinicians and researchers, as they identify a readily available biomarker that may facilitate diagnosis, improve disease monitoring, and support clinical trial design in a rare cancer that predominantly affects young patients. In clinical practice, serum PCT measurement could be incorporated as a non-invasive adjunct to imaging for the diagnosis and longitudinal assessment of FLC, although prospective studies in larger and more diverse cohorts are needed to refine diagnostic cut-offs and confirm specificity.
{"title":"Serum procalcitonin: A novel tumor biomarker for diagnosis and disease monitoring in fibrolamellar hepatocellular carcinoma","authors":"Jean-Charles Nault, Claudia Campani, Theo Z. Hirsch, Ethan Neumann, Waqar Arif, Sandrine Imbeaud, Marina Baretti, Marianne Ziol, Sabrina Sidali, Pauline Roger, Manon Allaire, Mohamed Bouattour, Fabio Marra, Brice Fresneau, Neus Llarch, Jean-Marie Peron, René Gerolami, Eric Nguyen Khac, Pierre Nahon, Nathalie Ganne-Carrié, Jessica Zucman-Rossi","doi":"10.1016/j.jhep.2026.01.015","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.01.015","url":null,"abstract":"<h3>Introduction</h3>Fibrolamellar carcinoma (FLC) is a rare primary liver cancer that predominantly affects young patients with normal known serum tumor biomarkers. An observation of an elevated procalcitonin (PCT) in one patient prompted us to investigate PCT as a biomarker in a larger cohort of FLC.<h3>Methods</h3>We measured serum PCT levels in 34 samples from 18 patients with FLC and in 64 patients with hepatocellular carcinoma (HCC), 24 with cholangiocarcinoma (CCA), and 20 with cirrhosis. Using RNA sequencing, we analyzed <em>CALCA</em> expression, encoding PCT, in 27 FLC tumors, 331 HCC tumors, 39 CCA tumors, 71 hepatoblastomas, 34 hepatocellular adenomas, and 55 non-tumor livers. Spatial transcriptomics was performed on three FLC and PCT immunohistochemistry on 13 FLC and 34 other primary or secondary liver cancers.<h3>Results</h3>In 8 FLC from the European cohort, median serum PCT was significantly elevated (55.2 μg/l) compared to patients with HCC (0.14 μg/l), CCA (0.16 μg/l), and cirrhosis (0.11 μg/l; P=0.0005). It was validated in a U.S. cohort of 10 FLC patients compared to HCC and CCA (P=0.0002). Across these cohorts, elevated serum PCT was observed in 83% of FLC cases versus 3% of HCC and CCA (P<0.0001). In four patients, changes in serum PCT levels correlated with radiologic response according to RECIST 1.1. RNA sequencing demonstrated significant overexpression of <em>CALCA</em> in FLC compared to other primary liver tumors (P<0.0001), and spatial transcriptomics localized <em>CALCA</em> expression specifically to tumor cells. Immunohistochemistry confirmed PCT overexpression in 77% of FLC but not in other liver cancers.<h3>Conclusion</h3>Procalcitonin is a sensitive and specific serum biomarker for FLC among primary liver cancers, with potential utility in diagnosis and monitoring of treatment response.<h3>Impact and implications</h3>This study is justified by the lack of reliable serum biomarkers for fibrolamellar carcinoma and demonstrates that procalcitonin is specifically overexpressed by FLC tumor cells and detectable in the blood of the patients with FLC. These findings are important for clinicians and researchers, as they identify a readily available biomarker that may facilitate diagnosis, improve disease monitoring, and support clinical trial design in a rare cancer that predominantly affects young patients. In clinical practice, serum PCT measurement could be incorporated as a non-invasive adjunct to imaging for the diagnosis and longitudinal assessment of FLC, although prospective studies in larger and more diverse cohorts are needed to refine diagnostic cut-offs and confirm specificity.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"92 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134199","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}
Pub Date : 2026-02-05DOI: 10.1016/j.jhep.2026.01.013
Disruption of the intestinal barrier facilitates microbial translocation to the liver and contributes to chronic liver disease. We aimed to study the …
肠道屏障的破坏促进了微生物向肝脏的易位，并导致慢性肝病。我们的目的是研究……
{"title":"Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease","authors":"","doi":"10.1016/j.jhep.2026.01.013","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.01.013","url":null,"abstract":"Disruption of the intestinal barrier facilitates microbial translocation to the liver and contributes to chronic liver disease. We aimed to study the …","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"3 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122075","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}
Pub Date : 2026-02-04DOI: 10.1016/j.jhep.2026.01.002
Valerie Chew
{"title":"Hepatic zonation as the gatekeeper of β-catenin oncogenic transformation","authors":"Valerie Chew","doi":"10.1016/j.jhep.2026.01.002","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.01.002","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"62 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109998","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}
Pub Date : 2026-02-03DOI: 10.1016/j.jhep.2026.01.017
Matthias Pinter, Massimo Iavarone
{"title":"Reversing the global burden of hepatocellular carcinoma","authors":"Matthias Pinter, Massimo Iavarone","doi":"10.1016/j.jhep.2026.01.017","DOIUrl":"https://doi.org/10.1016/j.jhep.2026.01.017","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"61 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110002","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}
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