JHEP Reports最新文献

{"title":"Pembrolizumab and stereotactic body radiotherapy combined in advanced hepatocellular carcinoma post sorafenib – A phase II trial (PEMRAD)","authors":"Grainne M. O’Kane ,&nbsp;Aruz Mesci ,&nbsp;Raymond W. Jang ,&nbsp;Aisling Barry ,&nbsp;Cynthia M. Bocaya ,&nbsp;Giselle M. Boukhaled ,&nbsp;Holly Acton ,&nbsp;David Doddington ,&nbsp;Rowena Rodrigo ,&nbsp;Leo M.L. Chan ,&nbsp;Babak Noamani ,&nbsp;Harry Harvey ,&nbsp;Andrew Elia ,&nbsp;Rhoda Law ,&nbsp;Rebecca Prince ,&nbsp;Mark Doherty ,&nbsp;Anna Dodd ,&nbsp;David K. Wong ,&nbsp;Lisa Wang ,&nbsp;Ben X. Wang ,&nbsp;Jennifer J. Knox","doi":"10.1016/j.jhepr.2025.101658","DOIUrl":"10.1016/j.jhepr.2025.101658","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>There is strong rationale for integrated approaches combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>The PEMRAD phase II trial investigated pembrolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced HCC following progression on sorafenib. Patients received pembrolizumab on Day 1, and SBRT commenced on Day 2. Up to 10 hepatic lesions (&lt;20 cm) were treated with SBRT. Pembrolizumab was continued every 21 days until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST v1.1, with a hypothesized improvement to 40% for the combination. Tissue and liquid biopsies were collected for correlative analyses, including immunohistochemistry, longitudinal blood cytometry by time-of-flight, and serum cytokine assessment.</div></div><div><h3>Results</h3><div>Between March 2018 and March 2023, 18 of a planned 22 patients were enrolled; 11 (61%) had macrovascular invasion (MVI) and 15 (83%) had extrahepatic metastases. Viral hepatitis was the underlying etiology in 50%. The ORR was 41% (95% CI 18–67%). Median progression-free survival was 5.4 months (2.8–9.9) and median overall survival was 12.6 months (5.7–25.8). Of 34 liver lesions treated with SBRT, only three progressed, in two patients. Among the 11 patients with MVI, 5 (45%) achieved a response, including one complete response. Treatment-related adverse events of grade ≥3 occurred in four patients (22%). One treatment-related death due to myocarditis was observed. Peripheral immunophenotyping showed that higher abundance of CD8⁺CD103⁺ T cells correlated with improved survival, whereas higher natural killer cell abundance was associated with inferior outcomes.</div></div><div><h3>Conclusion</h3><div>The combination of SBRT and pembrolizumab demonstrated a high response rate as second-line therapy for advanced HCC and warrants further evaluation, particularly in patients with MVI.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that combining stereotactic body radiotherapy with pembrolizumab is feasible and yields promising response rates in patients with advanced, previously treated hepatocellular carcinoma, including those with macrovascular invasion – a group typically associated with poor outcomes. These findings support further evaluation of this integrated approach and provide important guidance for the design of future clinical trials aimed at improving outcomes in advanced hepatocellular carcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101658"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978056","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":"Name MASLD/MASH — and act on it","authors":"Jeffrey V. Lazarus ,&nbsp;Mário G. Pessoa ,&nbsp;Debbie L. Shawcross ,&nbsp;Peter Schwarz ,&nbsp;Grace L. Su ,&nbsp;Simon Barquera","doi":"10.1016/j.jhepr.2025.101674","DOIUrl":"10.1016/j.jhepr.2025.101674","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101674"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146188946","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":"Orphan drug uttroside B impedes MASH progression and HCC development in experimental models","authors":"Tennyson P. Rayginia ,&nbsp;Chenicheri K. Keerthana ,&nbsp;Sreekumar U. Aiswarya ,&nbsp;Sadiq C. Shifana ,&nbsp;S. Jannet ,&nbsp;Sanjay Suresh Varma ,&nbsp;P. Maria Joy ,&nbsp;Mundanattu Swetha ,&nbsp;Shirly James ,&nbsp;J.S. Aparna ,&nbsp;Yadu Vijayan ,&nbsp;Archana Payickattu Retnakumary ,&nbsp;Lekshmi R. Nath ,&nbsp;Kalishwaralal Kalimuthu ,&nbsp;Vishnu Sunil Jaikumar ,&nbsp;Sankar Sundaram ,&nbsp;Nikhil Ponnoor Anto ,&nbsp;Noah Isakov ,&nbsp;Kuzhuvelil B. Harikumar ,&nbsp;Ravi S. Lankalapalli ,&nbsp;Ruby John Anto","doi":"10.1016/j.jhepr.2025.101626","DOIUrl":"10.1016/j.jhepr.2025.101626","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury, ultimately triggering chronic conditions, including fibrosis and cirrhosis, which may progress to hepatocellular carcinoma (HCC). Uttroside B (Utt-B), a phytosaponin isolated in our lab, has gained global recognition owing to its anti-HCC potential and is currently a United States FDA-designated ‘orphan drug’ against HCC. The present study highlights Utt-B as a propitious candidate drug against MASH and MASH-induced HCC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;MASH and MASH-induced HCC were developed in C57BL/6J mice using two distinct murine models: a high-fat diet model and a streptozotocin-induced steatohepatitis-derived HCC model, followed by i.p. administration of Utt-B. Protein expression analysis was performed using real-time quantitative reverse transcription-PCR and immunoblotting, while H&amp;E, Oil Red O, Sirius Red, and Masson’s Trichrome were utilized for staining cells/tissues. Nanostring n-Counter analysis was used to investigate the mechanism underlying the antifibrotic effects of Utt-B in MASH-induced HCC. Proliferation and apoptosis markers were also evaluated. Statistical analyses were conducted using R and GraphPad-Prism with significance set at &lt;em&gt;p&lt;/em&gt; &lt;0.05.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Utt-B ameliorated MASH-associated pathological features, including steatosis, hepatocyte ballooning, and inflammation (N = 6; non-alcoholic fatty liver disease activity score [NAS] &lt;2, &lt;em&gt;p&lt;/em&gt; &lt;0.0001). Utt-B upregulated the expression of autophagy markers autophagy-related 7 (ATG-7), Beclin-1, and microtubule-associated protein 1A/1B-light chain (LC3-II), and downregulated the expression of α-smooth muscle actin (α-SMA), which indicates the activation of hepatic stellate cells. Utt-B also halted the progression of MASH to HCC by hindering development of fibrosis with simultaneous inhibition of proliferative signals and induction of apoptosis in murine models (N = 6; NAS &lt;3, &lt;em&gt;p&lt;/em&gt; &lt;0.01).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Our investigation revealed effective impedance of MASH and its concomitant progression to HCC by Utt-B. Given the lack of anti-MASH drugs, these findings establish Utt-B as a potent drug for treating MASH and MASH-induced HCC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;MASH, stage IV of non-alcoholic fatty liver disease, can lead to chronic conditions, including fibrosis and cirrhosis, elevating the risk of HCC. Impaired lipid metabolism, inflammation, inhibition of autophagy, and dysregulated collagen and extracellular matrix biosynthesis are key factors contributing to the advance of MASH to HCC. Our discovery of Utt-B, a phytosaponin that exhibits remarkable anti-HCC potential and is a United States FDA-designated orphan drug against HCC, has gained global recognition. The present study","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101626"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034311","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":"Progressive fibrosis in human MASLD is associated with spatially linked transcriptomic signatures of metabolic reprogramming and senescence","authors":"Hani Vu ,&nbsp;Yuliangzi Sun ,&nbsp;Zherui Xiong ,&nbsp;Xiao Tan ,&nbsp;Daniel Radford-Smith ,&nbsp;Andrew Causer ,&nbsp;Alex M. Dickens ,&nbsp;Tuulia Hyötyläinen ,&nbsp;Ilia Evstafev ,&nbsp;Matej Oresic ,&nbsp;Christian Nefzger ,&nbsp;Eoin D. O’Sullivan ,&nbsp;Matthew J. Watt ,&nbsp;Grant A. Ramm ,&nbsp;Andrew Clouston ,&nbsp;Katharine M. Irvine ,&nbsp;Quan H. Nguyen ,&nbsp;Elizabeth E. Powell","doi":"10.1016/j.jhepr.2025.101657","DOIUrl":"10.1016/j.jhepr.2025.101657","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Granular detail about the location and nature of liver cell interactions and the metabolic, inflammatory and fibrogenic pathways driving progressive fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is needed to identify novel therapeutic targets.</div></div><div><h3>Methods</h3><div>We generated Visium spatial transcriptomic data from 33 human liver biopsies across the spectrum of MASLD. Gene expression data were overlaid with histological annotations to integrate spatial molecular and histopathological information, enabling interrogation of disease progression. Differential gene expression, pathway, cellular deconvolution and ligand-receptor interaction analyses were conducted for each annotated anatomical category, with specific protein expression validated using immunohistochemistry staining.</div></div><div><h3>Results</h3><div>Unsupervised clustering based on gene expression data classified the annotated spots into two main clusters enriched for fibro-inflammatory <em>vs</em>. parenchymal regions. Transcriptomic cellular deconvolution aligned well with manually annotated histopathological features. Fibrotic regions were enriched for genes involved in extracellular matrix/receptor interactions and inflammatory pathways (Benjamini-Hochberg adjusted <em>p</em> values &lt;0.05), underscoring known pathological mechanisms. We also identified immunoglobulin gene induction in late-stage fibrosis, which was spatially associated with a senescence signature, as has previously been reported in aging tissues. Dynamic changes in metabolic gene expression from early to late fibrosis were observed, suggesting MASLD progression is accompanied by a decline in normal liver metabolic function and reprogramming of metabolic fuel utilisation from oxidative to glycolytic metabolism, which may be both a cause and a consequence of senescence.</div></div><div><h3>Conclusions</h3><div>Taken together, our valuable discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD.</div></div><div><h3>Impact and implications</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has a complex pathogenesis driven by cell and matrix interactions in inflammatory niches. In this study, we identify a senescence signature in fibroinflammatory regions, characterised by high immunoglobulin expression and associated with a shift from oxidative to glycolytic metabolism. We identify spatially co-expressed ligand-receptor pairs, including senescence-associated factors, correlated with progressive fibrosis. This discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD and lays the groundwork for future research into the role of senescence in MASLD.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101657"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814289","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 to: “Extending the Baveno VII definition of recompensation to autoimmune hepatitis: Considerations regarding treatment timing and response criteria”","authors":"Yu Chen ,&nbsp;Xiao Xiao ,&nbsp;Xiong Ma","doi":"10.1016/j.jhepr.2025.101689","DOIUrl":"10.1016/j.jhepr.2025.101689","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101689"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146184613","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":"Practice changing RCT design and rationale: Abbreviated MRI plus AFP vs. ultrasound plus AFP for HCC surveillance in cirrhosis (PREMIUM study)","authors":"George N. Ioannou ,&nbsp;Tamar H. Taddei ,&nbsp;Beata M. Planeta ,&nbsp;Grant D. Huang ,&nbsp;Noel S. Weiss ,&nbsp;Timothy R. Morgan ,&nbsp;Jason A. Dominitz ,&nbsp;Ghassan K. Abou-Alfa ,&nbsp;Mustafa R. Bashir ,&nbsp;Michael V. Beheshti ,&nbsp;Amit G. Singal ,&nbsp;Cynthia A. Moylan ,&nbsp;Robin J. Boland ,&nbsp;Lynn F. Buchwalder ,&nbsp;Rajni L. Mehta ,&nbsp;Kimberly S. Hoisington ,&nbsp;Nhan V. Do ,&nbsp;Shari S. Rogal ,&nbsp;David E. Kaplan ,&nbsp;Jihane N. Benhammou ,&nbsp;Ifeyinwa Onyiuke","doi":"10.1016/j.jhepr.2025.101666","DOIUrl":"10.1016/j.jhepr.2025.101666","url":null,"abstract":"<div><div>Abdominal ultrasound every 6 months with or without serum alpha-fetoprotein (AFP) is recommended for hepatocellular carcinoma (HCC) screening in patients with cirrhosis. However, high-quality evidence demonstrating that this screening strategy reduces HCC-related mortality in cirrhosis is lacking. Dynamic contrast-enhanced abbreviated MRI (DCE aMRI) protocols for HCC screening have nearly identical performance to full multiphasic MRI (the gold standard for HCC diagnosis) and can be completed in under 15 min. PREMIUM is a multicentre randomised controlled trial comparing HCC screening by ultrasound+AFP every 6 months <em>vs.</em> DCE aMRI+AFP every 6 months for up to 8 years among patients with cirrhosis. Sponsored by and executed within the Department of Veterans Affairs (VA), participant recruitment began in November 2023. Eligible participants are Veterans aged 18-75 years with cirrhosis, high HCC risk, Child-Turcotte-Pugh (CTP) score ≤9, model for end-stage liver disease (MELD) score ≤20, and no MRI contraindications or life-threatening comorbidities. The DCE aMRI protocol consists of T1-weighted axial pre-contrast and DCE sequences (arterial, portal, and 5-minute delayed) following administration of extracellular gadolinium-based contrast agent, plus a T2-weighted sequence between portal and delayed phases. PREMIUM aims to randomise 4,700 participants (2,350 in each arm), who will undergo per-protocol imaging and follow-up for up to 8 years. The primary outcome is HCC-related mortality. Secondary outcomes include HCC stage at diagnosis, receipt of potentially curative HCC treatment, and all-cause mortality. The study is powered to detect at least a 35% relative reduction in HCC-related mortality in the aMRI+AFP arm <em>vs</em>. the ultrasound+AFP arm. If PREMIUM demonstrates reduced HCC-related mortality in the aMRI+AFP arm, it could provide the necessary evidence to recommend aMRI+AFP for HCC screening in patients with cirrhosis (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> identifier: NCT05486572).</div><div>The PREMIUM Study is a registered clinical trial: NCT05486572.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101666"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034431","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":"Extending the Baveno VII definition of recompensation to autoimmune hepatitis: Considerations regarding treatment timing and response criteria","authors":"Benedikt S. Hofer ,&nbsp;Lukas Burghart ,&nbsp;Thomas Reiberger ,&nbsp;Albert F. Stättermayer","doi":"10.1016/j.jhepr.2025.101667","DOIUrl":"10.1016/j.jhepr.2025.101667","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101667"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034366","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":"FGF1 ameliorates hepatic steatosis through acute activation of the unfolded protein response and VLDL production","authors":"Tim van Zutphen ,&nbsp;Dicky Struik ,&nbsp;Weilin Liu ,&nbsp;Sihao Liu ,&nbsp;Benan Pelin Sermikli ,&nbsp;Justina C. Wolters ,&nbsp;Henkjan J. Verkade ,&nbsp;Annette R. Atkins ,&nbsp;Michael Downes ,&nbsp;Ronald M. Evans ,&nbsp;Johan W. Jonker","doi":"10.1016/j.jhepr.2025.101660","DOIUrl":"10.1016/j.jhepr.2025.101660","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, &lt;em&gt;p &lt;&lt;/em&gt;0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, &lt;em&gt;p &lt;&lt;/em&gt;0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, &lt;em&gt;p &lt;&lt;/em&gt;0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, &lt;em&gt;p &lt;&lt;/em&gt;0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, &lt;em&gt;p &lt;&lt;/em&gt;0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerati","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101660"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814290","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":"Self-supervised learning to predict intrahepatic cholangiocarcinoma transcriptomic classes on routine histology","authors":"Aurélie Beaufrère ,&nbsp;Tristan Lazard ,&nbsp;Rémy Nicolle ,&nbsp;Gwladys Lubuela ,&nbsp;Jérémy Augustin ,&nbsp;Miguel Albuquerque ,&nbsp;Baptiste Pichon ,&nbsp;Camille Pignolet ,&nbsp;Victoria Priori ,&nbsp;Nathalie Théou-Anton ,&nbsp;Mickael Lesurtel ,&nbsp;Mohamed Bouattour ,&nbsp;Kévin Mondet ,&nbsp;Jérôme Cros ,&nbsp;Julien Calderaro ,&nbsp;Thomas Walter ,&nbsp;Valérie Paradis","doi":"10.1016/j.jhepr.2025.101675","DOIUrl":"10.1016/j.jhepr.2025.101675","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The transcriptomic classification of intrahepatic cholangiocarcinoma (iCCA) has recently been refined from two to five classes, each associated with pathological features, targetable genetic alterations, and survival outcomes. Despite its potential prognostic and therapeutic value, the transcriptomic classification is not routinely used in practice because of technical limitations, including insufficient tissue material and the high cost of molecular analyses. Here, we assessed a self-supervised learning (SSL) model for predicting iCCA transcriptomic classes on digitised whole-slide images (WSIs)</div></div><div><h3>Methods</h3><div>Transcriptomic classes defined from RNA sequencing data were available for all samples. The SSL method (Giga-SSL) was used to train our model on a discovery set of 766 WSIs from 137 biopsies and 109 surgical specimens obtained from 246 patients, using a five-fold cross-validation scheme. The model was validated in The Cancer Genome Atlas (TCGA) cohort (n = 29) and a French external validation set (n = 32), both using WSIs from surgical samples.</div></div><div><h3>Results</h3><div>The most frequent transcriptomic class was the hepatic stem-like class (37% [90/246] in the discovery set). Our model showed good to very good performance in predicting the four most frequent transcriptomic classes in the discovery set (AUC 0.63-0.84), especially for the hepatic stem-like class (AUC 0.84). The model performed equally well in predicting these transcriptomic classes in the two validation sets, with AUCs ranging from 0.76 to 0.80 in the TCGA set and 0.62 to 0.92 in the French external set.</div></div><div><h3>Conclusions</h3><div>We developed and validated an SSL-based model capable of predicting iCCA transcriptomic classes from routine histological slides of both biopsy and surgical samples. This approach may facilitate the clinical implementation of transcriptomic classification, improve prognostic assessment, and guide therapeutic decision-making in iCCA.</div></div><div><h3>Impact and implications</h3><div>Predicting transcriptomic classes directly from routine histological slides has the potential to enhance the clinical management of intrahepatic cholangiocarcinoma, enabling more accurate prognostication and supporting therapeutic decision-making. By eliminating the need for manual slide annotation, large tissue samples, or resource-intensive molecular analyses, our self-supervised learning-based model offers a practical and scalable solution that can be applied to both biopsy and surgical specimens. This approach could accelerate the adoption of transcriptomic classification in everyday practice and help guide more personalized treatment strategies for patients with intrahepatic cholangiocarcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101675"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814291","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":"Evaluation and Management of Primary Sclerosing Cholangitis Patients Awaiting Liver Transplantation","authors":"A.D. Frolkis ,&nbsp;J.S. Nayagam ,&nbsp;A. Parente ,&nbsp;M. Seager ,&nbsp;M.D. Sadler ,&nbsp;A.J. Montano-Loza ,&nbsp;D. Joshi","doi":"10.1016/j.jhepr.2026.101748","DOIUrl":"10.1016/j.jhepr.2026.101748","url":null,"abstract":"<div><div>Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic liver disease characterized by biliary strictures, increased risk of cholangiocarcinoma, and a strong association with inflammatory bowel disease. Despite its low prevalence, PSC accounts for up to 17% of all liver transplants (LT) performed globally. Transplant-free survival ranges from a median of 9 to 21 years from diagnosis. LT is the only definitive treatment with post-LT survival in PSC exceeding 80% at 5 years. However, PSC recurs in approximately 25% of individuals. The absence of disease modifying therapy necessitates timely LT in select cases of hepatic decompensation, refractory pruritus, recurrent cholangitis, or selected early-stage malignancies. However, PSC poses unique challenges in pre-transplant assessment and timing due to its clinical heterogeneity and the suboptimal performance of conventional prognostic tools such as the MELD score. Although PSC specific scores offer improved risk stratification, they are not integrated into routine LT algorithms.</div><div>This review synthesizes current landscape of prognostic modeling in PSC, focusing on validated tools and their role in transplant decision making. We examine the range of LT indications in PSC, explore the interplay between PSC and inflammatory bowel disease with attention to malignancy surveillance and immunosuppression planning. We review the transplant evaluation process, including hepatobiliary imaging, endoscopy, and multidisciplinary approaches to high grade stricture evaluation and oncologic risk assessment.</div><div>By integrating contemporary evidence and expert opinion, this review aims to guide clinicians in the nuanced assessment and management of PSC patients in the peri-transplant period, emphasizing the need for individualized risk assessment and early referral to transplantation centres with hepatobiliary surgery and transplant expertise.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 4","pages":"Article 101748"},"PeriodicalIF":7.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147449983","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}