Journal of Hepatology最新文献

{"title":"Rat Hepatitis E Virus: An Emerging Challenge in Human Hepatitis","authors":"Katja Dinkelborg, Sébastien Lhomme, André Gömer","doi":"10.1016/j.jhep.2025.09.020","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.020","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Conclusion</h2>rHEV is an emerging zoonotic pathogen with many critical questions still unanswered. In this issue, Lo et al. provide important new insights into its zoonotic risk (Box 1). Integration of rHEV testing in Hong Kong identified 22 human infections, while nearly doubling the number of complete human-derived rHEV genomes and enabling an open-access classification system for novel strains. Their findings indicate both adaptation to the human host and genotype-wide zoonotic potential, and the</section></section><section><section><h2>Authors’ contributions</h2>K.D., S.L., and A.G.: Writing – original draft and Writing – review &amp; editing.</section></section><section><section><h2>Financial support</h2>The authors did not receive any financial support to produce this manuscript.</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors do not have a conflict of interest to report.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"76 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209777","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":"Prognostic value of liver stiffness measurement vs. biochemical response in primary biliary cholangitis","authors":"Yu Jun Wong, Laurent Lam, Pierre-Antoine Soret, Sara Lemoinne, Bettina Hansen, Gideon Hirschfield, Aliya Gulamhusein, Ellina Lytvyak, Albert Pares, Ignasi Olivas, Maria-Carlota Londono, Sergio Rogriguez-Tajes, John E. Eaton, Karim T. Osman, Christoph Schramm, Marcial Sebode, Ansgar W. Lohse, George Dalekos, Nikolaos Gatselis, Frederik Nevens, Aldo J. Montano-Loza","doi":"10.1016/j.jhep.2025.09.024","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.024","url":null,"abstract":"<h3>Background/aim</h3>Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis (PBC). However, the frequency and clinical relevance of discordant biochemical and LSM changes remain unclear. We aim to determine the performance of the most recent or current LSM (LSMc) in predicting first hepatic decompensation (HD) in the setting of discordant biochemical and LSM responses.<h3>Methods</h3>In this international, multicenter study, we included patients with at least two reliable LSM performed at least six months apart. Patients with prior HD, liver transplantation (LT) or hepatocellular carcinoma were excluded. Biochemical response was based on the Paris-2 criteria. LSM response was defined as stable or any reduction in LSM. The primary outcome was the occurrence of the first HD. Secondary outcomes were LT and liver-related death. The influence of LSM on HD was estimated using Cox regression analysis.<h3>Results</h3>A total of 1,793 PBC patients were analyzed. Over a median follow-up of 22 (IQR: 12-39) months, 3.3% developed HD. Up to 55% of PBC patients exhibited discordance between LSM and biochemical response. Among patients with LSM response, achieving Paris-2 criteria was associated with a lower risk of HD (HR 0.25, 95%CI: 0.06-0.97, p&lt;0.044). Among patients with biochemical response, LSM response did not influence the risk of developing HD (HR 0.64, 95%CI: 0.21-1.96, p=0.429). The LSMc &gt;10 kPa strongly predicted HD (HR 14.5, 95% CI 6.9-30.6, p&lt;0.001), irrespective of biochemical response and prior LSM trajectories.<h3>Conclusions</h3>Discordance between LSM and biochemical response is frequent. Most recent or current LSM is the strongest predictor of first liver-related events in patients with PBC, irrespective of prior biochemical response or LSM trajectory.<h3>IMPACT AND IMPLICATIONS</h3>Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis (PBC). However, the clinical relevance and how discordant biochemical and LSM changes should be best interpreted remain unclear. In this large international multicenter study, we demonstrated that once the current LSM (LSMc) is known, prior LSM trajectories and biochemical changes did not improve the prediction of liver-related events in patients with PBC.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"26 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209776","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":"HES V2.0 validation and performance compared to GALAD and ASAP in the HEDS cohort","authors":"Hashem B. El-Serag, Camden Lopez, Michelle Luster, K.Rajender Reddy, Neehar Parikh, Amit G. Singal, Jorge A. Marrero, Aaron P. Thrift, Jagpreet Chhatwal, Ziding Feng, Stephanie Page-Lester, Qingchun Jin, Nabihah Tayob, Fasiha Kanwal","doi":"10.1016/j.jhep.2025.09.023","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.023","url":null,"abstract":"<h3>Background</h3>We previously developed Hepatocellular Carcinoma Early Detection Screening (HES) V2.0, biomarker panel (age, ALT, platelets, etiology, AFP, AFP L3, DCP and their gradient over the past one year) for early detection of HCC among patients with cirrhosis. We externally validated HES V2.0 and compared its performance to HES V1.0, GALAD, and ASAP.<h3>Methods</h3>We conducted a prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) cohort study in the HEDS (Hepatocellular Carcinoma Early Detection Strategy) 1,485 cirrhosis cohort (119 developed HCC). Patient- and test-level true positive rate (TPR) for HCC were calculated at 6, 12, 24 months before HCC diagnosis based on a threshold at a fixed false positive rate (FPR) of 10% and 18.1% - the latter corresponded to GALAD cut-off of -1.36.<h3>Results</h3>HES V2.0 and GALAD had same AUROC (0.79) but different TPR/FPRs. At the FPR of 10%, HES V2.0 had 2.0%, 6.7%, and 6.0% higher TPR (sensitivity) than GALAD within 6, 12, and 24 months before HCC diagnosis (one-sided p-values 0.24, 0.025, 0.078, respectively). At 18.1% FPR, GALAD had 6% and 2% higher sensitivity than HES V2.0 within 6 and 12 months before HCC and similar sensitivity within 24 months before HCC diagnosis (all p-values &gt;0.05).The sensitivity for HES V2.0 was 11.9% higher than HES V1.0 at 12 months (p=0.007). The sensitivity for HES V2.0 was considerably (10.9-16.3%) higher than ASAP. For patients with available labs to calculate gradients over time, the sensitivity of HES V2.0 was 3.5-8.7% higher than GALAD at all time points of testing before HCC (8.7% to 24.0% relative increase) with p&lt;0.05 for several comparisons.<h3>Conclusions</h3>In a phase 3 biomarker validation study, HES V2.0 had higher sensitivity than ASAP for HCC detection, and a similar or higher sensitivity than GALAD only at 12 months before HCC diagnosis at 10% FPR and when over time gradients in AFP, AFP L3, and DCP are available.<h3>Impact and Implications</h3>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with early detection being critical for improving survival outcomes. This study provides a rigorous phase 3 validation of the HES V2.0 biomarker panel, demonstrating its superior or comparable sensitivity to established models like GALAD and ASAP in a large, diverse U.S. cirrhosis cohort. The findings are particularly impactful for clinicians and researchers focused on liver cancer surveillance, as HES V2.0 offers enhanced detection performance, especially when longitudinal biomarker data are available. These results support the integration of HES V2.0 into clinical workflows and future trials, potentially improving early HCC detection and enabling timely curative interventions for at-risk patients.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"10 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203978","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":"Reversal of ACLF and ALF using whole blood extracorporeal system combining HLA-depleted liver organoids with granulocyte-monocyte apheresis","authors":"Hitomi Yamaguchi, Yosuke Yoneyama, Kentaro Ichimura, Kanae Ohtsu, Mika Soen, Chiharu Moriya, Maki Kumagai, Robert P. Myers, G. Mani Subramanian, Takanori Takebe","doi":"10.1016/j.jhep.2025.08.038","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.08.038","url":null,"abstract":"<h3>Background &amp; Aims</h3>Acute-on-chronic liver failure (ACLF) is characterized by catastrophic loss of liver function in patients with advanced chronic liver disease, with 28-day mortality rates reaching up to 80%. Despite advances in intensive care, the high mortality primarily stems from the absence of a therapeutic modality that simultaneously addresses both the profound systemic inflammatory response and severe hepatic synthetic dysfunction.<h3>Methods</h3>We designed an integrated extracorporeal circuit, termed the UTOpiA system, which combines granulocyte and monocyte apheresis (GMA) with human induced pluripotent stem cell-derived hepatocyte-like cell (iHLC) organoids engineered with HLA-A, HLA-B, and CIITA triple knockout. The efficacy of UTOpiA was tested after direct whole blood exposure through venous flow in rat models of ACLF and acute liver failure (ALF).<h3>Results</h3>UTOpiA treatment significantly improved survival in both ACLF and ALF rat models, outperforming GMA or iHLC monotherapy and HepG2 cell-based devices. Improved survival was associated with reduced coma severity, improved liver biochemistry, and reduced hyperammonaemia, hyperbilirubinemia, and systemic inflammation. Transcriptomic and histological analyses revealed restoration of hepatic metabolic gene expression and hepatocyte regeneration. Mechanistically, iHLC-secreted α-fetoprotein suppressed hepatocyte cell cycle arrest via p21 downregulation and enhanced regeneration, while UTOpiA restored HNF4α activity and dampened pro-inflammatory cytokines, including IL-6 and TNF-α.<h3>Conclusions</h3>The tandem UTOpiA circuit confers a significant survival benefit in preclinical rodent models of ACLF and ALF by providing anti-inflammatory, synthetic, and metabolic support. Elucidating the regenerative signals that promote recovery of the injured liver may further expand the potential of this whole blood extracorporeal system as a novel, off-the-shelf liver support therapy.<h3>Impact and implications</h3>Restoring hepatic metabolism while controlling inflammation in acutely decompensated cirrhosis remains a major unmet clinical need. By combining HLA-modified human induced pluripotent stem cell–derived liver organoids with granulocyte and monocyte apheresis, we developed a bioartificial liver system that manages inflammation, restores liver function, and promotes regeneration in two rat models of severe liver failure. This therapy could offer an off-the-shelf treatment option for patients with life-threatening liver failure.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"114 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203994","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":"Targeting cell-state plasticity driven by FOXM1/CEBPB axis disrupts developmental heterogeneity and therapeutic resistance in hepatocellular carcinoma","authors":"Xiao-Feng Zhang, Xiao-Yu Zuo, Yun Zhu, Jia-Xu Li, Jie-Shen Xian, Wen-Xin Zhang, Wei Cheng, Jun Yuan, Yuan-Feng Gong, Hui Tang, Xu-Qi Yang, Ying-Yue Su, Cheng-Yang Zhang, Shan-Shan Liu, Li Huang, Heng Wang, Mei-Mei Li, Shao-Yan Xi, Yun-Qiang Tang, Lei Zhou, Ming Liu","doi":"10.1016/j.jhep.2025.09.022","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.022","url":null,"abstract":"<h3>Background &amp; Aims</h3>Heterogeneous cellular states traverse the developmental hierarchy induced by phenotypic plasticity and are emerging as key drivers of therapeutic resistance in HCC. However, the factors governing this developmental heterogeneity are not clear, and therapeutic interventions are lacking.<h3>Methods</h3>Autoregulatory network analysis was performed on public datasets of bulk RNA-seq and scRNA-seq data from patients with HCC, as well as on our hepatocyte differentiation model, to identify key transcriptional regulators governing the transition of cellular states during hepatic differentiation. <em>In vitro</em> and <em>in vivo</em> models were used to investigate molecular mechanisms and evaluate therapeutic potential.<h3>Results</h3>We demonstrate dynamic cell–state transitions with chaotic developmental trajectories in the malignant progression of hepatocellular carcinoma. High developmental diversity is closely linked to the activation of drug resistance genes and immune evasion, significantly affecting patient prognosis. We identify that the FOXM1/CEBPB axis at the apex controls developmental heterogeneity dynamics. They form a master decision toggle switch by mutually suppressing each other and competing for control over downstream state-specific networks. Inhibiting FOXM1 restores tumor developmental homogeneity, exposing tumor cells back to immune surveillance. The likely mechanism is the activation of IFN-γ signaling and antigen presentation. A GalNAc-conjugated, chemically modified siRNA lead compound targeting hepatic FOXM1 is designed and shows strong potency and tolerability in therapeutic mouse models.<h3>Conclusion</h3>Tumor cell–state plasticity driven by the FOXM1/CEBPB axis induces developmental heterogeneity and therapeutic resistance in hepatocellular carcinoma. RNAi-based therapies targeting hepatic FOXM1 showed strong potential for further clinical testing.<h3>Impact and Implications</h3>Tumor heterogeneity and therapeutic resistance remain major barriers in cancer treatment, largely driven by dynamic transitions across multiple cellular states. This study reveals that the FOXM1/CEBPB axis is a crucial regulator of these hierarchical cellular transitions and plays a key role in sustaining developmental heterogeneity and promoting resistance to therapies. By targeting this axis, we demonstrated the restoration of developmental homogeneity and significant disruption of therapeutic resistance in preclinical models. Furthermore, our findings highlight the strong efficacy of RNAi-based therapeutics directed at hepatic FOXM1, highlighting their promising potential as pioneering small nucleic acid drugs for cancer therapy.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"157 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203942","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":"Transcriptomic and epigenetic mechanisms controlling cholangiocytes transdifferentiation into hepatocytes","authors":"Vasileios Galanakis, Christopher Gribben, Andi Munteanu, Marta Cagna, Floris J.M. Roos, Cristian Bulgaru, Liviu Ciortuz, Michael Allison, Irina Mohorianu, Ludovic Vallier","doi":"10.1016/j.jhep.2025.09.021","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.021","url":null,"abstract":"<h3>Background &amp; Aims</h3>The liver’s ability to regenerate is well established, yet the mechanisms involved in chronic liver disease remain to be fully uncovered. Recent animal and human studies showed that transdifferentiation between cholangiocytes and hepatocytes could play a role in this process. Here, we uncover the molecular mechanisms that drive this cellular plasticity in human patients.<h3>Methods</h3>We derived intrahepatic cholangiocytes organoids from the three liver lobes of end-stage MASH patients. The resulting organoid lines were differentiated into biphenotypic cells expressing hepatocyte markers mimicking the transdifferentiation process occurring during chronic injury <em>in vivo</em>. We then combined single-nuclei RNAseq and single-nuclei ATACseq to uncover molecular pathways and epigenetic regulations required for the in vitro conversion of cholangiocytes into hepatocytes. These analyses led to the identification of transcription factors regulating this process.<h3>Results</h3>Our analyses suggest that cholangiocyte plasticity is independent of their liver location and that specific lobes are unlikely to be more regenerative than others. Single-nuclei ATAC sequencing analyses identify the opening of chromatin in intrahepatic cholangiocyte organoids as a mechanism of plasticity, while functional validations reveal that the transcription factor HNF4G could play a key role in the induction of hepatocyte markers. The relevance of these findings was validated against single-nuclei RNA sequencing data from liver biopsies of patients with end-stage MASH disease.<h3>Conclusions</h3>Overall, our results confirm that cholangiocytes can transdifferentiate into hepatocytes. This process is promoted by HNF4G, it involves epigenetic remodelling, and is consistent across the three liver lobes. This knowledge paves the way for future therapies aiming to enhance liver regeneration by increasing cholangiocytes' plasticity.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"100 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARG inhibition halts cholangiocarcinoma progression via the Hippo pathway and enhances response to chemotherapy and immunotherapy","authors":"Mincheng Yu, Peiyi Xie, Qiang Yu, Yufei Zhao, Wenxin Xu, Zhangfu Yang, Yujuan Wei, Binghai Zhou, Shuang Liu, Sanyuan Dong, Yongfeng Xu, Yongsheng Xiao, Bo Zhang, Lei Guo, Qinghai Ye, Hui Li","doi":"10.1016/j.jhep.2025.09.018","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.018","url":null,"abstract":"<h3>Background &amp; Aims</h3>Cholangiocarcinoma (CCA) is a fatal malignancy with limited therapeutic options. We sought to investigate the oncogenic role of poly(ADP-ribose) glycohydrolase (PARG) and test potential therapeutic strategies.<h3>Methods</h3>A tissue microarray comprising 275 CCA patient samples was analyzed by immunohistochemistry. Liquid chromatography–tandem mass spectrometry was utilized to identify downstream targets of PARG. Transgenic mice (<em>Parg</em>^<em>f/f</em>) were employed to establish spontaneous CCA model via hydrodynamic tail vein injection (HTVi) and biliary instillation (BI). The efficacy of PARG inhibition was tested in various CCA preclinical models, including patient derived organoids (PDOs), patient-derived xenograft (PDX), an immunocompetent syngeneic murine model, and orthotopic xenograft models. Cytometry by time of flight (CyTOF) analysis was utilized to profile the changes in tumor microenvironment following PARG inhibition and anti-PD-1 therapy.<h3>Results</h3>PARG is highly expressed in CCA and predicts a dismal prognosis based on analysis of a large patient cohort. Genetic depletion of <em>Parg</em> in spontaneous CCA models induced by two methods, including HTVi and BI, significantly halted carcinogenesis. PARG inhibition alone showed impressive efficacy and potentiated Gem/Cis in PDOs, PDX, and orthotopic models. Mechanistically, PARG dePARylates and suppresses ITCH autoubiquitination, thus inhibiting the Hippo pathway, which promotes CCA proliferation and chemoresistance. Moreover, CyTOF analysis revealed the crosstalk between the tumor and stroma, which could be suppressed by PARG inhibitors via TEADs/CXCR4/CXCL12 axis. Combining PD-1 blockade and Gem/Cis with PARG inhibitors resulted in a significantly greater reduction in tumor burden, as well as a survival benefit.<h3>Conclusions</h3>Targeting PARG limits CCA progression, alleviates desmoplasia, and enhances response to both anti-PD-1 therapy and chemotherapy.<h3>Lay summary</h3>Little is known about the role of PARG in CCA development and progression. Herein, we show that PARG expression is upregulated and hyperactivated in CCA, promoting tumor cell proliferation, cancer-associated fibroblast recruitment, and resistance to therapy. Pharmacological inhibition of PARG suppresses CCA development and could be an effective therapeutic strategy when combined with chemotherapy and immunotherapy.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"61 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II INTEGRIS-PSC trial of bexotegrast, an αvβ6/αvβ1 integrin inhibitor, in primary sclerosing cholangitis","authors":"Gideon M. Hirschfield, Kris V. Kowdley, Palak J. Trivedi, Bertus Eksteen, Bilal Hameed, Catherine Vincent, Tianyan Chen, Aparna Goel, K.Gautham Reddy, Eric Orman, Deepak Joshi, Éric A. Lefebvre, Johanna R. Schaub, Mahru C. An, Annie Clark, Chris N. Barnes, Richard Pencek, Douglas Thorburn, Aldo J. Montano-Loza, Christoph Schramm, Cynthia Levy","doi":"10.1016/j.jhep.2025.09.016","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.09.016","url":null,"abstract":"<h3>Background &amp; Aims</h3>Transforming growth factor-β signaling activated by α_vβ₆ and α_vβ₁ integrins drives liver fibrosis in primary sclerosing cholangitis (PSC). This study investigated the safety and exploratory pharmacodynamics of bexotegrast (PLN-74809), an oral, once-daily inhibitor of α_vβ₆ and α_vβ₁ integrins, in participants with PSC and liver fibrosis.<h3>Methods</h3>In this Phase 2, double-blind, dose-ranging study, 117 participants with PSC were randomized 3:1 to receive once-daily oral bexotegrast or placebo in 3 cohorts (40 mg or placebo for 12 weeks [part 1]; 80 mg, 160 mg, or placebo for 12 weeks [part 2]; and 320 mg or placebo for ≤40 weeks [part 3]). The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Exploratory pharmacodynamic endpoints included changes in alkaline phosphatase values, enhanced liver fibrosis (ELF) scores, neoepitope-specific N-terminal pro-peptide of type III collagen levels, liver stiffness measurements, magnetic resonance imaging (MRI) measures using gadoxetate, and the Itch Numeric Rating Scale.<h3>Results</h3>A total of 117 participants received bexotegrast (40 mg [n=22], 80 mg [n=21], 160 mg [n=21], 320 mg [n=27]) or placebo (n=30). Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (72.7% and 70.0%). TEAEs were mild to moderate, and no serious TEAEs related to study drug were observed. Numerically less pharmacodynamic progression was observed with bexotegrast in ELF score, PRO-C3, and MRI assessments at Week 12 compared with placebo. Pharmacodynamic results at Week 24 showed limited change from Week 12 except in MRI parameters which continued to improve.<h3>Conclusions</h3>Bexotegrast was well tolerated in participants with PSC and liver fibrosis for up to 40 weeks with numerically less progression observed in exploratory pharmacodynamic markers.<h3>Trial registration number</h3>NCT04480840<h3>Primary source of funding</h3>Pliant Therapeutics, Inc.<h3>Impact and Implications</h3>Primary sclerosing cholangitis (PSC) is a rare cholestatic disease of unknown etiology. Currently, there is an unmet medical need for safe and effective therapies capable of halting or reversing progression of PSC. In this Phase 2 study in participants with PSC and suspected liver fibrosis, bexotegrast, an oral, once-daily, dual selective inhibitor of α_vβ₆ and α_vβ₁ integrins, had a favorable safety and tolerability profile. This study supports targeting integrin-mediated transforming growth factor-β activation as a potential therapeutic approach for PSC.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"74 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141158","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":"Anticoagulant therapy to delay disease progression in patients with cirrhosis – reponse to Acka et al., Bot et al. and Feng et al.","authors":"Ton Lisman, Ángela Puente, Juan Carlos García-Pagán","doi":"10.1016/j.jhep.2025.08.043","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.08.043","url":null,"abstract":"No Abstract","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"12 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140554","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":"Kupffer cells are regulators of intergenerational signalling in MASLD","authors":"Prakash Ramachandran","doi":"10.1016/j.jhep.2025.08.027","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.08.027","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Background and context</h2>The concept of the DOHaDs (developmental origin of health and diseases) implicates early life events, particularly those occurring during foetal development, in long-term health and the risk of developing certain non-communicable diseases in later life.¹ A poor <em>in utero</em> environment has been associated with a range of metabolic diseases in adults,² whilst maternal obesity is also linked to other conditions such as neuropsychiatric disorders in offspring.³ An increased risk of metabolic</section></section><section><section><h2>Objectives, methods and findings</h2>In a recent article by Huang <em>et al.</em> published in <em>Nature</em>, the authors aimed to explore the impact of maternal obesity on offspring KC phenotype and the risk of developing MASLD.⁷ To unpick the interplay between maternal gestational effects, the modulation of lactation by diet and direct dietary responses following weaning, they established a complex mouse model whereby mothers were fed either control diet (CD) or high-fat diet (HFD), resultant offspring were cross-fostered by lactating mothers</section></section><section><section><h2>Significance of findings</h2>This novel work highlights the potential role of KCs as sensors of the intrauterine environment and orchestrators of intergenerational responses in the liver. Similar data has been described for long-lived resident macrophages in the brain,³^,⁵ suggesting that macrophage reprogramming in different tissues may represent a fundamental part of the DOHaD paradigm.The highly elegant and complex studies presented by Huang <em>et al.</em> can only be carried out in model animals. However, there remains an</section></section><section><section><h2>Financial support</h2>P.R. was funded by an MRC Senior Clinical Fellowship (MR/W015919/1).</section></section><section><section><h2>Conflict of interest</h2>The authors of this study declare that they do not have any conflict of interest.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"28 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140553","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}