JHEP Reports最新文献

{"title":"Hepatic encephalopathy in chronic liver disease: Emerging insights from the gut microbiome.","authors":"Yevedzo Ntuli, Maria Nehme Ibrahimi, Victoria Tatiana Kronsten, Debbie Lindsay Shawcross","doi":"10.1016/j.jhepr.2026.102022","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102022","url":null,"abstract":"<p><p>Hepatic encephalopathy remains an underserved complication of chronic liver disease. Reliable diagnostic and prognostic biomarkers linked to disease pathophysiology are currently lacking, as are options for treatment that reduce mortality beyond lactulose and rifaximin. However, with the advent of high-throughput sequencing and multi-omics techniques to interrogate microbial taxonomy and metabolic pathways, our understanding of the gut-liver-brain-axis has moved beyond the ammonia-inflammation hypothesis. This review summarises recent studies that have aimed to characterise the role of the gut-liver-brain axis in hepatic encephalopathy and how this can be leveraged to create novel diagnostic, prognostic and therapeutic agents.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102022"},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887282","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":"Perioperative strategies for the treatment of HCC.","authors":"Antonio D'Alessio, Felix J Krendl, Alessandro Parente, Rebecca Marino, Maria Guerra Veloz, Parissa Tabrizian","doi":"10.1016/j.jhepr.2026.102021","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102021","url":null,"abstract":"<p><p>Curative-intent treatments for hepatocellular carcinoma (HCC), including liver resection and transplantation, are limited by high recurrence rates and strict patient selection criteria. The success of immune checkpoint inhibitors (ICIs) in advanced disease has driven their integration into the perioperative setting, with the aim of improving long-term outcomes and expanding access to curative strategies. Neoadjuvant immunotherapy represents a biologically attractive approach, leveraging the intact tumour microenvironment to enhance systemic antitumour immunity and eradicate micrometastatic disease. Early-phase trials have demonstrated feasibility and promising efficacy outcomes, while recent phase 2/3 data suggest improved event-free survival with perioperative ICI-based combinations (CARES-009 trial), but no survival benefit with adjuvant ICI alone (IMbrave050 trial). In parallel, conversion strategies incorporating ICIs with tyrosine kinase inhibitors and locoregional therapies are increasing resectability rates in selected patients with initially unresectable disease. In the transplant setting, ICIs show potential as a bridging or downstaging strategy, although concerns regarding allograft rejection and optimal washout intervals remain. Emerging biomarkers, including pathological response and circulating tumour DNA, may refine patient selection and guide the design of adaptive clinical trials. Collectively, these advances support a shift toward biomarker-driven, perioperative immunotherapy strategies to optimise curative-intent management of HCC.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102021"},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887375","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":"Medical therapy of MASLD - consequences of the paradigm shift from histology to non-invasive tests.","authors":"Eva Katharina Messer, David Petroff, Katsutoshi Sugimoto, Philip N Newsome, Fuminori Moriyasu, Shalimar, Marco Dioguardi Burgio, Cosmin Sebastian Voican, Valérie Vilgrain, Victor de Lédinghen, Daniel Jesper, Stephan Baumeler, Deike Strobel, Wah Kheong Chan, Edward G Grant, Gabriel Perlemuter, Linda C Kelahan, Ana-Carolina Cardoso, Helena Gabriel, Sandeep Aggarwal, Byung Ihn Choi, Peter J Eddowes, Takashi Nishimura, Michael Allison, Hiroko Iijima, Emmanuel Tsochatzis, Theodore J Dubinsky, Quentin M Anstee, Jing Gao, David Sheridan, Dong Ho Lee, Jeremy F Cobbold, Jae Young Lee, Sylvie Naveau, Yanan Zhao, David Semela, Pintong Huang, Grace Lai-Hung Wong, Jie Zeng, Vincent Wai-Sun Wong, Adrian Lim, Cristiane A Villela-Nogueira, Xiaoyan Xie, Harshit Garg, Richard G Barr, Vito Cantisani, Giovanna Ferraioli, Kentaro Sakamaki, Takao Itoi, Masayoshi Kage, Hirohisa Yano, Valentin Blank, Johannes Wiegand, Thomas Karlas","doi":"10.1016/j.jhepr.2026.101996","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101996","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;The recent approval of pharmacological therapies for fibrotic metabolic dysfunction-associated steatohepatitis (MASH) has increased the need for accurate identification of treatment-eligible patients. Current recommendations increasingly rely on non-invasive tests (NITs), including vibration-controlled transient elastography (VCTE), while multiparametric ultrasound (MPUS) may provide additional opportunities for non-invasive assessment. However, agreement between histology and imaging-based approaches remains uncertain. We compared treatment eligibility based on histology, VCTE, and MPUS in two international biopsy-proven cohorts of metabolic dysfunction-associated steatotic liver disease (MASLD).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We analysed two biopsy-proven MASLD cohorts: CAP-IPDMA (n=1029), including VCTE and controlled attenuation parameter (CAP), and iLEAD (n=124), including MPUS. Treatment eligibility was assessed using histologically confirmed F2/F3 MASH and NIT-based recommendations from international expert panels.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In CAP-IPDMA, 277/1029 patients (26.9%) met the histological definition of \"at-risk MASH\". Depending on the VCTE cut-off, 13.2-32.0% qualified for treatment. Overlap between histological \"at-risk MASH\" and VCTE thresholds was limited, reaching 27.8% when using VCTE 8-15 kPa, and decreasing when narrower or higher thresholds were applied. Among patients identified only by VCTE 8-15 kPa, males had lower median AST and ALT than those fulfilling only the histological indication (35 vs 48 IU/L p=0.034 and 45 vs 62 IU/L p=0.0072, respectively). In iLEAD, 21/124 patients (16.9%) met the histological definition, while 13.7-16.1% were eligible based on SWE thresholds, again with a similarly limited overlap.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Histology and non-invasive tests capture partly distinct patient populations, meaning that both the number and type of patients selected for therapy depend on the chosen modality and cutoffs. As vibration-controlled transient elastography and multiparametric ultrasound become increasingly accessible in clinical practice, prospective validation is essential for establishing reliable non-invasive treatment pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;The current literature reflects a paradigm shift away from biopsy-based approaches toward NIT-based assessment of treatment eligibility in metabolic dysfunction-associated steatotic liver disease (MASLD), which may substantially affect which patients receive newly approved therapies. Our results are important for clinicians, researchers, and guideline developers because histology and current NIT cut-offs identify only partially overlapping patient populations, implying that different diagnostic strategies select different risk profiles. In practice, these findings support thoughtful implementation of NIT-based treatment pathways, the use of repeated measurements, and pros","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101996"},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887320","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":"Refined liver MRI-derived cT1 thresholds capturing hepatic fat fraction enhance mortality risk prediction.","authors":"Minsun Kwak, Abdelrahman M Attia, Mohammad Saeid Rezaee-Zavareh, Yufeng Wang, Lixia Wang, Walid S Ayoub, Alexandar Kuo, Paul Martin, Hirsh D Trivedi, Aarshi Vipani, Yun Wang, Stephen Pandol, Debiao Li, Shelly C Lu, Hyun-Seok Kim, Ju Dong Yang","doi":"10.1016/j.jhepr.2026.101927","DOIUrl":"10.1016/j.jhepr.2026.101927","url":null,"abstract":"<p><strong>Background & aims: </strong>Corrected T1 (cT1), measured by liver MRI, enables non-invasive assessment of hepatic water content. Although a threshold of ≥800 ms has been proposed to identify individuals at risk of metabolic dysfunction-associated steatohepatitis (MASH) and adverse outcomes, it identifies only a small proportion of individuals (∼5%) and may fail to capture risk below this threshold. We aimed to evaluate whether cT1 values below 800 ms are associated with mortality and whether hepatic steatosis, assessed by MRI-derived proton density fat fraction (PDFF), modifies this association.</p><p><strong>Methods: </strong>We analyzed 29,597 UK Biobank participants with liver MRI-derived cT1 measurements. Participants were categorized into three groups (<700, 700-799, and ≥800 ms) based on penalized spline analysis. Outcomes included all-cause mortality, cause-specific mortality, and liver-related events. Cox proportional hazards models were adjusted for demographic, lifestyle, and cardiometabolic factors.</p><p><strong>Results: </strong>Approximately 40% of participants had cT1 values of 700-799 ms, and 5% had cT1 values ≥800 ms. Over a median follow-up of 5.3 years, participants with cT1 values of 700-799 ms had higher risks of all-cause mortality (adjusted hazard ratio [aHR] 1.21; 95% CI 1.02-1.43) and cardiovascular mortality (aHR 1.54; 95% CI 1.04-2.28) than those with cT1 values <700 ms. Risks were even higher among participants with cT1 values ≥800 ms. Clinically significant hepatic steatosis (PDFF ≥10%) significantly modified the association between cT1 and all-cause mortality (p for interaction <0.05). Higher cT1 was associated with increased all-cause mortality only among participants with PDFF <10% (aHR 1.25 [95% CI 1.06-1.49] for cT1 700-799 ms and 2.20 [95% CI 1.40-3.48] for cT1 ≥800 ms, compared with cT1 <700 ms), but not among those with PDFF ≥10%.</p><p><strong>Conclusion: </strong>cT1 values between 700 and 799 ms were independently associated with an increased risk of mortality. Notably, this association was modified by the presence of clinically significant hepatic steatosis as assessed by PDFF.</p><p><strong>Impact and implications: </strong>Using liver MRI to measure cT1, we demonstrated that cT1 values of 700-799 ms, below the conventional threshold of 800 ms, were independently associated with an increased risk of all-cause and cardiovascular mortality. We also found that this association was present only among participants with PDFF <10%, indicating that clinically significant hepatic steatosis modifies the relationship between cT1 and mortality. These findings suggest that lower cT1 thresholds may improve risk stratification and that the prognostic significance of cT1 should be interpreted in the context of hepatic steatosis.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101927"},"PeriodicalIF":8.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Metabolomic Panel for Noninvasive Screening of Biopsy-Confirmed MASH in Children and Adolescents.","authors":"Helaina E Huneault, Shrramana Ganesh Sudhakar, Alasdair E Gent, Zachery R Jarrell, Matthew Ryan Smith, Cristian Sanchez-Torres, Ajay K Jain, Katherine P Yates, Brent A Neuschwander-Tetri, Jeffrey B Schwimmer, Stavra A Xanthakos, Jean P Molleston, Cynthia A Behling, Mark H Fishbein, Rishikesan Kamaleswaran, Miriam B Vos","doi":"10.1016/j.jhepr.2026.102016","DOIUrl":"10.1016/j.jhepr.2026.102016","url":null,"abstract":"<p><strong>Background & aims: </strong>Noninvasive tests to identify pediatric metabolic dysfunction-associated steatohepatitis (MASH) remain a critical need. We aimed to develop and validate a screening panel that identifies biopsy-confirmed MASH in children and adolescents using clinical and metabolomics data.</p><p><strong>Methods: </strong>Fasting serum from youth in NASH CRN studies and healthy participants underwent untargeted metabolomics by liquid chromatography-mass spectrometry (LC-MS). Clinical data included anthropometrics, lipids, liver enzymes, and markers of insulin resistance. MASH was determined by biopsy in NASH CRN participants and hepatic steatosis by MRI-PDFF in healthy participants. Clinical features were selected by Kolmogorov-Smirnov testing (p < 0.05), and metabolomics data were reduced to 52 features with non-zero LASSO coefficients. Feature importance was ranked using CatBoost. The final model included eight clinical features and the top 10 annotated metabolites. Data were split into training and test sets, with longitudinal validation in a sub-cohort with 96-week follow-up biopsies.</p><p><strong>Results: </strong>The cohort included 586 children (ages 5-18, 70% male, mean BMI z-score of 2.35 ± 0.84, 72% Hispanic). Of these, 390 had MASH (21% Zone 3, 41% Zone 1, 38% definite MASH), and 196 were non-MASH. The model incorporated ALT, AST, GGT, platelets, HOMA-IR, BMI z-score, TG:HDL ratio, and alkaline phosphatase. Key metabolic features included amino acid derivatives (e.g., glutamic acid, argininosuccinic acid), indole, diacetylspermine, and lipid metabolites. The model achieved an AUROC of 0.88 (92% sensitivity, 71% specificity) in the test set and 0.81 (69% sensitivity, 86% specificity) in the longitudinal cohort.</p><p><strong>Conclusions: </strong>This 18-variable panel of eight clinical measures and 10 metabolites showed strong performance for noninvasive screening of biopsy-confirmed MASH in children and potential utility for longitudinal monitoring.</p><p><strong>Impact and implications: </strong>Currently, there are no clinically approved non-invasive biomarkers for diagnosing or monitoring pediatric MASH, despite its growing prevalence and long-term health risks. This study developed and validated a machine-learning-based panel that combines clinical and high-resolution metabolomics data, demonstrating strong performance for classifying MASH and monitoring disease status in a longitudinal cohort. These findings are particularly relevant for improving the care of children with MASH and could inform both clinical practice and research. With further validation, this approach could reduce reliance on liver biopsy, enable earlier detection, and support clinical decision-making for physicians and researchers.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102016"},"PeriodicalIF":8.7,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860471","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":"Multi-ancestry sequencing analysis in 293,141 participants identifies predisposition DNA repair genes associated with HCC risk.","authors":"Alexis M Garofalo, Perapa Chotiprasidhi, Josephine Princy Johnson, Karina Sato-Espinoza, Jun Ma, Hunter Miller, Daniel O'Brien, Lindsay Guare, Katie M Cardone, Nicole Palmiero, Zachary Rodriguez, David E Kaplan, Julie A Lynch, Philip S Tsao, Daniel J Rader, Lewis R Roberts, Jose D Debes, Emuobor Odeghe, Funmilayo Lesi, Ganiyat Oyeleke, Ângelo Z Mattos, Marco Arrese, Enrique Carrera, Jhon Prieto, Andre Boonstra, Javier Diaz-Ferrer, Edith N Okeke, Jun Wang, Lifang Hou, Adwoa Agyei-Nkansah, Mary Yeboah Afihene, Yaw Asante Awuku, Albert Nyanga, Kyong-Mi Chang, Samuel O Antwi, Marijana Vujković, Anurag Verma, Kirk J Wangensteen","doi":"10.1016/j.jhepr.2026.102019","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102019","url":null,"abstract":"<p><strong>Background & aims: </strong>Genetic testing for Lynch and BRCA1/2-associated hereditary cancer syndromes is recommended in colon or pancreatic cancer patients, but their association with hepatocellular carcinoma (HCC) risk is unknown. We evaluated associations between rare germline variants in DNA-repair genes and HCC risk across ancestrally diverse cohorts.</p><p><strong>Methods: </strong>We analyzed whole exome (WES) and whole genome sequencing (WGS) data from 2,594 HCC cases and 290,547 cancer-free controls from diverse biobanks and cohorts: Penn Medicine BioBank, All of Us, Mayo Clinic, ESCALON, and the Million Veteran Program. Participants were classified into six population groups. We focused on six DNA-repair genes previously implicated in HCC: BRCA2, BRIP1, MSH6, PMS2, CHEK2, and FANCA. Gene-level burden analyses of rare predicted loss-of-function (pLoF) and damaging missense variants were performed in European and African populations, and across all six ancestry groups.</p><p><strong>Results: </strong>In the European population, MSH6, a Lynch syndrome-associated gene, had the strongest association with HCC, with a 2.75-fold increased HCC risk at 1% minor-allele frequency (MAF) (OR= 2.75 [1.50, 5.04], P=0.001, FDR q=0.02), while PMS2, showed a nominally significant association at the same MAF threshold (OR=1.90 [1.08, 3.34], P=0.03, FDR q=0.09). Combined analysis across all populations strengthened the MSH6 finding (OR=2.53 [1.43, 4.49], P=0.001, FDR q=0.01) at a MAF of 0.1%. A significant BRCA2 association was also observed in the combined analysis at a MAF of 0.1% (OR=2.26 [1.39, 3.67], P=0.001, FDR q=0.01).</p><p><strong>Conclusions: </strong>Rare variants in MSH6 and BRCA2 are significantly associated with increased HCC risk, revealing a previously unconfirmed role for DNA repair genes in HCC susceptibility across ancestrally diverse populations. These findings may inform genetic risk stratification and surveillance strategies.</p><p><strong>Impact and implications: </strong>Rare variants in MSH6 and BRCA2 genes are associated with 2.3 to 2.8-fold higher HCC risk. These findings may warrant further evaluation of liver cancer risk in individuals with MSH6-associated Lynch syndrome or BRCA2-associated hereditary cancer syndromes.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102019"},"PeriodicalIF":8.7,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857440","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":"MiR-122 regulates liver tolerance.","authors":"Maytal Gefen, Shanny Layani, Emma Klahr, Zohar Shemuelian, Johannes Brandi, Thomas Jacobs, Christiane Steeg, Lorenz Adlung, Christoph Kilian, Merav Ordan, Oren Gordon, Nathalie Abudi, Rinat Abramovitch, Yuval Nevo, Sharona Elgavish, Hadar Benyamini, Jonathan Monin, Elina Zorde Khvalevsky, Nofar Rosenberg, Aurelia Markezana, Dayana Yaish, Adi S Yehezkel, Alina Simerzin, Mila Rivkin, Osher Amran, Daniel S Goldenberg, Amnon Peled, Jonathan Axelrod, Jacob Rachmilewitz, Samuel Huber, Nicola Gagliani, Christoph Schramm, Sören Weidemann, Johannes Herkel, Antonella Carambia, Rifaat Safadi, Abed Khalaileh, Ashraf Imam, Daniela Heide, Jenny Hetzer, Stefan Rose-John, Mathias Heikenwälder, Hilla Giladi, Eithan Galun","doi":"10.1016/j.jhepr.2026.102020","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102020","url":null,"abstract":"<p><strong>Background and aims: </strong>The liver is an immune privileged organ, yet it needs to overcome infections. We aimed to explore the role of the liver-specific microRNA miR-122 in liver immune tolerance.</p><p><strong>Methods: </strong>We developed a miR-122 knockout (KO) mouse model and assessed immune, inflammatory, and fibrogenic responses from early postnatal stages. Innate and adaptive immune alterations were studied in miR-122 KO mice. Transcriptomic profiles from autoimmune hepatitis (AIH) patients were compared to these KO mice.</p><p><strong>Results: </strong>MiR-122 KO mice developed liver inflammation and fibrosis as early as two weeks of age. An inverse correlation between miR-122 expression and inflammation/fibrosis was observed in both KO mice (p<0.01in both at weeks two (n=6) and three (n=6) of KO mice age) and human AIH samples (p<0.01, n=9). KO mice shared transcriptomic and phenotypic features with human AIH. RNA sequencing identified over 5,000 differentially expressed genes between wt and KO mice, including upregulated chemokines, immune checkpoints, and pro-fibrotic markers. IRF2, a TLR3 transcription factor, was identified as a novel direct target of miR-122.</p><p><strong>Conclusions: </strong>MiR-122 is a key regulator of liver immune tolerance, modulating inflammation and fibrosis via distinct pathways. Its absence enhances immune activation and accelerates fibrosis. These findings identify miR-122 as a promising therapeutic target for autoimmune liver diseases.</p><p><strong>Impact and implication: </strong>The liver is an immune-privileged organ, an adaptation likely evolved to prevent robust immune responses against material absorbed from the gastrointestinal tract. This tolerance creates a sanctuary for pathogens-including bacteria, hepatitis viruses, and parasites such as Plasmodium-within the liver parenchyma, and similarly permits the development of primary liver malignancy and metastatic seeding. We found that miR-122 regulates hepatic immune tolerance, positioning miR-122 modulation as a potential therapeutic strategy for infectious, autoimmune, malignant, and metastatic liver diseases.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102020"},"PeriodicalIF":8.7,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857447","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 extracellular vesicles for early cholangiocarcinoma detection in primary sclerosing cholangitis.","authors":"Ainhoa Lapitz, Marit M Grimsrud, Elisa Catanzaro, Pedro M Rodrigues, Johannes R Hov, Mikel Azkargorta, Beatriz Val, Mette Vesterhus, Krzysztof Grzyb, Henrik Mikael Reims, Felix Elortza, Laura Izquierdo-Sánchez, María J Perugorria, Luis Bujanda, Lars Aabakken, Vemund Paulsen, Tom H Karlsen, Jesus M Banales, Trine Folseraas","doi":"10.1016/j.jhepr.2026.102003","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102003","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Cholangiocarcinoma (CCA) is a major complication of primary sclerosing cholangitis (PSC), with a 20-year incidence of ∼15%. Early detection is challenging, as current surveillance rarely identifies CCA at a resectable stage. This study investigated bile-derived extracellular vesicles (EVs) as a liquid biopsy source for protein biomarkers enabling early diagnosis and prediction of CCA in PSC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Bile samples were collected from PSC (n=52), PSC with concomitant CCA (PSC-CCA; n=14), and PSC patients who later developed CCA (PSC to CCA; n=8). EV proteomes were analyzed by mass spectrometry. Multivariable logistic regression models were used to evaluate diagnostic performance. Biomarker expression was assessed in CCA single-cell RNA sequencing (scRNA-seq) datasets, and selected proteins were validated in total serum by ELISA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Proteomic analysis identified 15 EV-proteins that distinguished PSC-CCA from PSC independently of demographic and clinical factors. A four-protein machine learning model (COPA, ATP5H, VTNC, PRDX2) combined with serum CA19-9 achieved high diagnostic performance for PSC-CCA in our cohort (AUC=0.993), outperforming CA19-9 alone (AUC=0.801). A separate three-protein panel (TM9S4, ATPO, KINH) showed potential for early identification of PSC patients who later developed CCA, prior to clinical or radiological detection, with an internally estimated sensitivity of 100% and specificity of 97%, whereas CA19-9 showed no predictive value. COPA, VTNC, and PRDX2 were validated in total serum by ELISA, and scRNA-seq supported the expression of these markers in malignant cholangiocytes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Bile EVs contain protein biomarkers with promising diagnostic value and potential utility for risk stratification of future CCA development in individuals with PSC. Pending further external validation, as bile collection may be performed during routine ERCP procedures, this liquid biopsy approach could facilitate earlier detection, timely interventions, and improved outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Primary sclerosing cholangitis (PSC)-associated cholangiocarcinoma (CCA) remains a major clinical challenge, burdened by ineffective surveillance strategies and poorly sensitive diagnostic tools. This exploratory study identifies bile extracellular vesicle (EV) protein signatures with promising diagnostic performance and potential value for short-term risk stratification or early detection, including biomarker panels that enhance standard CA19-9 performance and detect malignancy prior to clinical or radiological diagnosis. The detectability of some of these biomarkers by ELISA supports their technical feasibility and potential clinical applicability. These findings require validation in larger, independent cohorts before clinical implementation can be considered; if externally validated, bile EV-based biomarker","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102003"},"PeriodicalIF":8.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148793243","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":"Management of rare primary liver cancers: combined hepato-cholangiocarcinoma and fibrolamellar hepatocellular carcinoma.","authors":"Matteo Gallant, Marie Decraecker, Marianne Ziol, Julien Calderaro, Maxime Ronot, Jessica Zucman-Rossi, Jean-Charles Nault","doi":"10.1016/j.jhepr.2026.101991","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101991","url":null,"abstract":"<p><p>Fibrolamellar hepatocellular carcinoma (FLC) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) are rare primary liver cancers for which limited evidence is available to guide clinical management. cHCC-CCA could arises in the context of chronic liver disease and shares epidemiological and molecular features with both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), reflecting its intermediate biological and clinical position between these two entities. Its diagnosis remains challenging particularly when based on tumor biopsy specimens. Surgical resection remains the standard of care when feasible. Liver transplantation, trans-arterial chemoembolization, ablation, or selective internal radiation therapy have been used in selected cases. For advanced disease, systemic treatments commonly used for HCC or CCA have been applied in real-world practice, including platinum-based chemotherapy, tyrosine kinase inhibitors, and more recently immunotherapy. In addition, molecularly guided therapies have been explored, as targetable genetic alterations can be identified in a subset of cHCC-CCA. In contrast, FLC typically arises in non-cirrhotic livers of young patients and is frequently associated with metastatic disease, including lymph node involvement. At the molecular level, FLC is characterized by the presence of the DNAJB1-PRKACA fusion and by elevated serum procalcitonin secreted by the tumor. Surgical resection remains the cornerstone of treatment when feasible, but data guiding systemic therapy in unresectable cases are limited. Several regimens, including gemcitabine-oxaliplatin, lenvatinib, and immunotherapy, have been evaluated. More recently, clinical trials have reported antitumor activity with combinations of immunotherapy and vaccines targeting the DNAJB1-PRKACA fusion. To improve patient care, since cHCC-CCA and FLC are rare subtypes of liver cancer, we need to compile prospective samples and clinical data from the patients, including their response to any type of treatment at the national and international levels.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101991"},"PeriodicalIF":8.7,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760288","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":"Combined anti-PD-1 with irreversible electroporation relieves immunosuppression and reduces hepatocellular carcinoma regrowth.","authors":"Jihui Huo, Lina Wang, Kai Lei, Weishan Luo, Zongren Wang, Hongtao Zhu, Gaomin Zheng, Youmei Kang, Wenjie Huang, Xiaoxue Ren, Yingdong Hou, Cong Liang, Tao Yang, Manxia Lin, Xiaoxing Li, Sui Peng, Ming Kuang, Han Xiao, Shuling Chen, Zihao Dai","doi":"10.1016/j.jhepr.2026.101977","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101977","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Local ablation triggers anti-tumor response and is regarded as an encouraging treatment combined with immunotherapy for hepatocellular carcinoma (HCC). Irreversible electroporation (IRE) is a novel ablative technique eliminating tumor cells by electroporation, however, the characteristics of IRE-induced immune microenvironment and underlying mechanism remain unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We developed an orthotopic immunocompetent HCC mouse model and performed incomplete IRE-ablation. The post-IRE immune microenvironment was characterized by RNA sequencing, single-cell RNA sequencing, flow cytometry, and multiplex immunofluorescence. Cytokine-chemokine array and organoid-immune cell co-culture were used to investigate the functions and underlying mechanism. The combination therapy of IRE and anti-PD-1 was examined for HCC treatment in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;IRE initially inhibited HCC growth, but tumors rapidly regrew by day 14 after ablation, with increased Ly6G&lt;sup&gt;+&lt;/sup&gt; Polymorphonuclear (PMN) Myeloid-Derived Suppressor Cells (MDSCs) infiltration and CD8&lt;sup&gt;+&lt;/sup&gt; T cell exhaustion. In patient-derived HCC organoids, IRE-induced CD8&lt;sup&gt;+&lt;/sup&gt; T cell cytotoxicity was suppressed by MDSCs. Ly6G antibody-mediated PMN-MDSC depletion repressed HCC regrowth after IRE-ablation in vivo (1.29±0.12 vs 0.49±0.09 g, p&lt;0.001). Mechanistically, HCC cells degraded CXCL10 mRNA via YTH N&lt;sup&gt;6&lt;/sup&gt;-methyladenosine RNA binding protein F2 (YTHDF2), which activated MDSCs that led to CD8&lt;sup&gt;+&lt;/sup&gt; T cells exhaustion. Combined anti-PD-1 and IRE reduced tumor burden by 84.3% compared with IRE alone (0.22±0.08 vs 1.43±0.13 g, p&lt;0.01), prolonged survival (day-60 survival: 93.33% vs 40%, p&lt;0.001), and induced long-term anti-tumor immunity in mice. Four unresectable recurrent HCC patients treated with IRE plus anti-PD-1 therapy showed improved recurrence-free time than patients receiving IRE alone.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;PMN-MDSCs mediated immunosuppression that promoted HCC regrowth after incomplete IRE ablation. Combining anti-PD-1 therapy is a promising approach to eliminate post-ablation residual HCC, supporting evaluation in prospecitve clinical trials.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Post-ablation recurrence remains a major challenge in HCC. Here, we show that although IRE initially activates CD8&lt;sup&gt;+&lt;/sup&gt; T cells but subsequently promotes PMN-MDSCs activation and CD8&lt;sup&gt;+&lt;/sup&gt; T-cell exhaustion through YTHDF2-mediated CXCL10 mRNA degradation, resulting in a suppressive tumor immune microenvironment (TIME). These findings identify a previously unrecognized mechanism of post-IRE tumor regrowth and provide a rationale for early combination with anti-PD-1 therapy. Although further prospective clinical validation is required, this work suggests that monitoring post-ablation immune changes and applying rational immunotherapy combinations may help optimize treatment s","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101977"},"PeriodicalIF":8.7,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669568","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}