JHEP Reports最新文献

{"title":"Development and Psychometric Evaluation of the Liver Disease Stigma Scale (LDSS).","authors":"Wei Zhang, Edward Wu, Kelly Hsu, Cassidy Sun, Toshali Katyal, Ana Ivkovic, Heidi Yeh, Emily Bethea, Sarah Wakeman, Russell Goodman, Jay Luther, Cristal Brown, Robert Wong, Esperance Schaefer, Raymond T Chung, Nneka Ufere, Annie B Fox","doi":"10.1016/j.jhepr.2026.101870","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101870","url":null,"abstract":"<p><strong>Background & aims: </strong>Chronic liver disease (CLD) is increasingly prevalent, and stigma remains a barrier to care, particularly for alcohol-associated liver disease (ALD). No validated instruments measure liver disease-specific stigma. We developed and evaluated the Liver Disease Stigma Scale (LDSS).</p><p><strong>Methods: </strong>We conducted a cross-sectional study of 211 patients from inpatient and outpatient hepatology services at a tertiary center. Participants were categorized as alcohol-associated liver disease (ALD; n=128) or non-ALD (n=83). The LDSS assessed internalized, anticipated (family and healthcare), and experienced (family and healthcare) stigma. Psychometric evaluation included exploratory factor analysis (EFA), internal consistency (Cronbach's alpha), and convergent validity with the Substance Use Stigma Mechanisms Scale (SU-SMS) and mental health symptoms. Known-groups validity was assessed using t-tests and adjusted linear regression.</p><p><strong>Results: </strong>EFA supported a five-factor structure accounting for 73.7% of variance. Subscale reliability was excellent (α = 0.90-0.97). LDSS subscales showed strong convergent validity with corresponding SU-SMS subscales (r = 0.43-0.80) and moderate correlations with mental health (r = 0.18-0.60). Known-groups validity was demonstrated by higher stigma scores among participants with ALD, particularly for internalized stigma (2.34 vs 1.50, p < 0.001, d = 0.85) and family-experienced stigma (1.80 vs 1.18, p < 0.001, d = 0.77). After adjustment, differences in internalized and family-experienced stigma remained significant.</p><p><strong>Conclusions: </strong>The LDSS demonstrated a stable five-factor structure, strong reliability, and good convergent validity, supporting its use as a psychometrically sound measure of liver disease-specific stigma. Patients with ALD showed higher stigma levels, underscoring the scale's clinical relevance and the need for further research on stigma and outcomes in liver disease. Findings require validation in larger, more diverse, and independent samples.</p><p><strong>Impact and implications: </strong>The Liver Disease Stigma Scale fills an important measurement gap by providing the first multidimensional instrument specifically developed to assess stigma among adults with chronic liver disease. Stigma levels were higher among individuals with alcohol associated liver disease, underscoring the relevance of stigma as a psychosocial factor that may influence engagement and wellbeing in this population. The scale provides a standardized and psychometrically robust approach for assessing stigma and offers a foundation for future research and quality improvement efforts aimed at identifying stigma burden and informing targeted clinical or behavioral strategies. These findings may help clinicians, researchers, and health systems more systematically understand how stigma shapes patient experience and consider approaches to promote mo","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101870"},"PeriodicalIF":7.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856373","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":"Elevated liver fat content is independently associated with insulin resistance in people with type 1 diabetes.","authors":"Jonathan Mertens, Maarten Spinhoven, Rie Braspenning, Floris Vanhevel, Eveline Dirinck, Christophe De Block, Sven Francque","doi":"10.1016/j.jhepr.2026.101887","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101887","url":null,"abstract":"<p><strong>Background: </strong>Insulin resistance is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) in the general population, but its relationship with MASLD in people with type 1 diabetes (T1D) remains insufficiently defined.</p><p><strong>Methods: </strong>We performed a 40 mU/m²/min hyperinsulinaemic-euglycaemic clamp (HEC) to quantify whole-body glucose disposal (M-value, mg/kg/min). Insulin sensitivity was further assessed using the 13C glucose breath test (13C-GBT) and the estimated glucose disposal rate (eGDR). Liver fat content (LFC) was measured by magnetic resonance spectroscopy, and vibration-controlled transient elastography was performed. Participants were stratified 1:1 by MASLD status based on mean LFC >/≤5.56%.</p><p><strong>Results: </strong>We studied 39 adults with T1D (diabetes duration 27±13 years; HbA1c 6.9 [6.5-7.8] %). Mean M-value was 4.41±2.37 mg/kg/min. LFC was higher in MASLD versus non-MASLD participants (8.2 [6.5-18.7] % vs. 3.0 [2.3-3.6] %, p<0.001). M-value was significantly lower in the MASLD group (2.92±1.39 vs. 6.41±2.46 mg/kg/min, p<0.001). LFC strongly correlated with the M-value (rs -0.72, p<0.001). In linear regression, the M-value independently predicted log-transformed LFC (B -0.22, p<0.001; R²=0.47). Lower M-value was associated with MASLD (adjusted OR 3.12, 95% CI 1.17-8.37, p=0.024). Both 13C-GBT (aOR 1.54, 95% CI 1.03-2.33, p=0.033) and eGDR (aOR 1.61, 95% CI 1.09-2.38, p=0.016) were also independently associated with MASLD.</p><p><strong>Conclusion: </strong>Insulin resistance is independently associated with MASLD in adults with T1D.</p><p><strong>Impact and implications: </strong>This study addresses the limited understanding of how MASLD relates to insulin resistance in T1D. We show a robust association between LFC and insulin resistance using gold standard and practical non-invasive measures. These findings may help clinicians identify metabolically at-risk individuals with T1D, although further research is required to clarify whether screening and targeted intervention improve outcomes.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101887"},"PeriodicalIF":7.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global Structural Determinants of MASLD: Development-Stratified Pathways Linking Food Systems, Metabolic Risk, and Liver Outcomes.","authors":"James M Paik, Markos Kalligeros, Shira Zelber-Sagi, Annette Paik, Saleh A Alqahtani, Zobair M Younossi","doi":"10.1016/j.jhepr.2026.101888","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101888","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Structural features of national food systems shape metabolic risk, yet their pathways to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) across development levels remain poorly characterized. We examined food-system pathways to MASLD prevalence and liver-related mortality across 204 countries.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A cross-national ecological study harmonized data from the Global Burden of Disease study, NCD Risk Factor Collaboration, and FAOSTAT. Exposures were anchored to 2005-2011, metabolic mediators to 2013-2015, MASLD prevalence to 2019-2021, and liver mortality to 2023. Countries were stratified by Sociodemographic Index (SDI; low &lt;0.60 vs high ≥0.60). Structural equation models estimated direct and indirect path associations among food-system characteristics, metabolic mediators, and liver outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In low-SDI countries (n=101), urbanization was associated with higher ultra-processed food retail exposure (β=+0.41), which was associated with higher obesity prevalence (β=+0.17). Food-price burden was inversely associated with caloric surplus (β=-0.44). Caloric surplus was associated with MASLD prevalence (β=+0.46). Political stability was inversely associated with MASLD prevalence (β=-0.31). In high-SDI countries (n=103), ultra-processed food exposure was associated with higher sugar kilocalorie share (β=+0.35), which was associated with higher obesity (β=+0.54). Cereal kilocalorie share was independently associated with higher type 2 diabetes (T2D) prevalence (β=+0.17). T2D was the dominant structural correlate of MASLD (β=+0.80). Healthcare Access and Quality index was positively associated with MASLD prevalence (β=+0.28) and inversely associated with MASLD mortality (β=-0.33). Healthcare quality was inversely associated with hepatitis B and hepatitis C mortality in both strata, but not alcohol-related liver disease mortality.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Structural pathways to MASLD differ by development level: ultra-processed food exposure and caloric surplus dominate in low-SDI settings, while T2D dominates in high-SDI settings. These findings identify development-specific intervention targets for reducing liver disease burden.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Food-system structural characteristics including ultra-processed food retail exposure, dietary composition, and food-price burden are differentially associated with MASLD prevalence through development-stratified pathways, providing a cross-national structural framework that extends beyond individual metabolic risk factors. These findings are relevant to global health researchers, epidemiologists, and policymakers working to understand and reduce rising liver disease burden in diverse economic settings. In low-SDI countries, efforts to monitor and moderate ultra-processed food retail expansion may warrant priority alongside caloric sufficiency programs; in high-","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101888"},"PeriodicalIF":7.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel pharmacological inhibitor of MAP4K4 activity attenuates metabolic dysfunction-associated steatohepatitis.","authors":"Felix Ampadu, Nikhil Patil, Venkateswararao Eeda, Iulia Rus, Woncheol Jung, Hassan M Abu Shukair, Anza Ali, Yuriana Aguilar-Sanchez, Tae Gyu Oh, Vibhudutta Awasthi, Aditya D Joshi","doi":"10.1016/j.jhepr.2026.101886","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101886","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive condition and a leading driver of global liver-related morbidity. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatic steatosis, inflammation, hepatocellular ballooning, and fibrosis. This study aimed to define the significance of MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4) as a therapeutic target and to evaluate a novel small-molecule inhibitor, glucosyl pyrrolo-pyrimidinone (GPPD), for the mitigation of MASH.</p><p><strong>Methods: </strong>MAP4K4 expression was immunohistochemically quantified in liver biopsies from healthy individuals (n=5) and MASLD patients (n=20). The in vitro efficacy of GPPD and genetic MAP4K4-silencing (siRNA) was assessed in human primary hepatocytes, mouse hepatic organoids, HepG2, and AML12 cells challenged with oleic acid. For in vivo validation, mice were fed a high-fat/high-fructose/high-cholesterol diet and treated with GPPD for 30-weeks (n=8/group). Livers were analyzed using single-nuclei RNA sequencing to identify the molecular mechanisms of GPPD-mediated hepatoprotection. Data was analyzed using ANOVA models and expressed as mean ± standard deviation (SD) with differences considered significant at p < 0.05.</p><p><strong>Results: </strong>Hepatic MAP4K4 expression was significantly elevated in MASLD patients compared to healthy controls, correlating with disease severity. In multiple in vitro models, both genetic silencing and GPPD treatment significantly attenuated steatosis. In vivo, prophylactic GPPD administration reduced body mass gain and adiposity while protecting against hepatic steatosis, inflammation, injury, and fibrosis. Mechanistically, while GPPD directly inhibited MAP4K4 activity, its hepatoprotective effects were associated with suppression of CaMK2 (calcium/calmodulin-dependent protein kinase II).</p><p><strong>Conclusions: </strong>Our results demonstrate that glucosyl pyrrolo-pyrimidinone treatment mitigates steatohepatitis with fibrosis by regulating MAP4K4-CaMK2 axis. Further investigation of GPPD will advance its development as an effective future therapeutic strategy against MASH.</p><p><strong>Impact and implications: </strong>This study identifies the MAP4K4-CaMK2 signaling axis as a critical pathway in the pathogenesis of MASH. By demonstrating that GPPD-mediated inhibition of this pathway attenuates key hallmarks of MASH - including steatosis, inflammation, and fibrosis - our findings provide a mechanistic framework for future therapeutic intervention. Moreover, targeting MAP4K4 may address significant unmet needs of patients who are ineligible for currently approved treatments. Collectively, this research establishes a translational foundation for the development of next-generation small molecules designed at restoring metabolic homeostasis across the disease continuum.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101886"},"PeriodicalIF":7.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837895","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":"Development of a CRISPR-Cas13-based antiviral strategy against hepatitis E virus.","authors":"Emely Richter, Mara Klöhn, Maximilian K Nocke, Marcel Edgar Friedrich, Daniel Todt, Eike Steinmann, Yannick Brüggemann","doi":"10.1016/j.jhepr.2026.101885","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101885","url":null,"abstract":"<p><strong>Background & aims: </strong>Effective antiviral drugs remain unavailable for many clinically relevant pathogens, including the hepatitis E virus (HEV). This study aimed to evaluate the CRISPR/Cas13d system as a potential antiviral strategy against HEV.</p><p><strong>Methods: </strong>We developed a reporter assay to screen CRISPR RNAs (crRNAs) targeting conserved regions of the HEV genome and tested their antiviral activity in human hepatoma cells using a robust HEV cell culture model. HEV replication was assessed using a subgenomic replicon, infectious particle production was quantified by immunofluorescence and titration assays. A bioinformatic analysis was performed to identify a minimal set of crRNAs capable of broadly targeting circulating human pathogenic HEV strains.</p><p><strong>Results: </strong>A crRNA screen identified multiple functional crRNAs targeting HEV-3, with ORF1-targeting crRNAs significantly reducing viral capsid expression (p < 0.01) and decreasing the number of HEV-infected cells (p < 0.01). Cas13d-mediated targeting led to robust reduction of HEV replication and markedly lowered infectious virus production in vitro (p < 0.001). Bioinformatic analysis revealed that just three distinct crRNAs could cover ∼95% of known HEV genomes with zero mismatches, while four crRNAs achieved complete coverage.</p><p><strong>Conclusions: </strong>Our findings demonstrate that CRISPR/Cas13d can target HEV replication and viral progeny production in vitro. The identification of a minimal crRNA set capable of broadly targeting circulating HEV strains suggests that the CRISPR/Cas13d system may offer an antiviral strategy to address challenges related to viral evolution and treatment escape.</p><p><strong>Impact and implications: </strong>This study establishes CRISPR/Cas13d as a proof-of-concept antiviral strategy against hepatitis E virus (HEV), demonstrating suppression of viral replication and particle production in vitro. By identifying a minimal set of broadly effective crRNAs, we provide a framework for targeting diverse HEV variants and buffering against viral evolution. These findings highlight the potential of CRISPR-based systems as innovative antiviral strategies.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101885"},"PeriodicalIF":7.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837920","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":"Recapitulation of Bile Acid Metabolism in Hepatobiliary Organoids Derived from hiPSC.","authors":"Junming Xu, Xiaopu Sang, Jie Ke, Jingyi Li, Jiasen Xu, Xiaoni Chen, Shan Lin, Ruijie Cai, Xianjie Shi, Fenfang Wu","doi":"10.1016/j.jhepr.2026.101884","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101884","url":null,"abstract":"<p><strong>Background & aims: </strong>Bile acids are crucial mediators of cholesterol homeostasis, lipid digestion, and detoxification, and reliable in vitro synthesis systems are essential for liver disease research and precision medicine. Although hiPSC-derived hepatic organoids model key human liver functions, fully recapitulating bile acid biosynthesis remains challenging. Here, we generated bile acid-hepatobiliary organoids (BA-HBOs) that capture major aspects of bile acid metabolism, thereby providing a more physiologically and pathologically relevant platform for metabolic studies and drug screening.</p><p><strong>Methods: </strong>Maturation protocols were optimized with saikosaponin A to enhance bile acid biosynthesis in BA-HBOs. Fibrotic BA-HBOs (FiBA-HBOs) were further established by TGF-β treatment. Cellular identity and functional markers were evaluated by immunofluorescence, flow cytometry, and qPCR. Organoid heterogeneity was characterized by single-cell RNA sequencing, and bile acid composition and diversity were quantified by LC-MS/MS metabolomics.</p><p><strong>Results: </strong>BA-HBOs demonstrated hepatic and biliary functions, including organized lineage segregation and robust synthetic and metabolic capacities. Compared with controls, BA-HBOs showed increased bile acid synthesis, improved bile duct structure, and higher transport protein expression (n ≥ 3, p < 0.05). Targeted metabolomics identified a complex spectrum of 33 bile acid species, predominated by glycine-conjugated forms, consistent with human physiology. Single-cell RNA sequencing revealed that BA-HBOs recapitulated the transcriptional landscape of adult liver tissue, and revealed hepatocyte subpopulation restructuring associated with enhanced bile acid metabolism. Moreover, modeling fibrosis-associated dysregulation generated FiBA-HBOs, which exhibited cholestasis-like changes and disease-relevant metabolomic profiles (n ≥ 3, p < 0.05).</p><p><strong>Conclusion: </strong>BA-HBOs recapitulate key aspects of human liver bile acid metabolism, hepatocyte zonation, and core metabolic processes in vitro, providing a physiologically relevant platform for mechanistic studies of liver disease and screening therapeutic candidates.</p><p><strong>Impact and implications: </strong>Our hiPSC-derived BA-HBOs synthesize and secrete diverse bile acid species, capturing key transcriptional and metabolic profiles of the human liver. They enable modeling of liver fibrosis accompanied by disruptions in bile acid metabolism, offering a tool to dissect disease mechanisms. These robust organoids create new opportunities for basic liver research, therapeutic development, and precision medicine.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101884"},"PeriodicalIF":7.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837918","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":"Editorial Board page","authors":"","doi":"10.1016/S2589-5559(26)00151-5","DOIUrl":"10.1016/S2589-5559(26)00151-5","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 5","pages":"Article 101880"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147850617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A thioacrylamide-based compound directly counteracts hepatic fibrosis with profound anti-obesity action","authors":"Elisabeth Rohbeck ,&nbsp;Corinna Niersmann ,&nbsp;Bedair Dewidar ,&nbsp;Karl Köhrer ,&nbsp;Thorsten Wachtmeister ,&nbsp;Bruno Guigas ,&nbsp;Volker M. Lauschke ,&nbsp;D. Margriet Ouwens ,&nbsp;Michael Roden ,&nbsp;Juergen Eckel","doi":"10.1016/j.jhepr.2026.101792","DOIUrl":"10.1016/j.jhepr.2026.101792","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Obesity-associated metabolic dysfunction–associated steatotic liver disease (MASLD) and its progression to steatohepatitis (MASH) with advanced fibrosis pose a major global health challenge. Targeting γ-aminobutyric acid (GABA)ergic system has shown promise in mitigating liver injury. Therefore, we investigated HK3, a positive allosteric modulator of the GABA&lt;sub&gt;A&lt;/sub&gt; receptor, as a potential therapy for MASH, with a particular focus on liver fibrosis and obesity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Human-derived 3D MASH spheroids (n = 4-27) and hepatic stellate cells (LX2, n = 3-5) were treated with increasing concentrations of HK3 or its derivative HK1 to assess their anti-steatotic, anti-inflammatory and anti-fibrotic efficacy. Molecular and transcriptional responses were assessed by immunoblotting, ELISA, reverse-transcription PCR and RNA sequencing. The &lt;em&gt;in vivo&lt;/em&gt; effects of HK3 (10 or 25 mg/kg) were evaluated in carbon tetrachloride-induced fibrosis (n = 10) or diet-induced obesity (n = 6-7) mouse models. Adipocytes (3T3-L1, n = 5-8) and visceral adipose tissue from C57BL/6 mice (n = 6) were treated with HK3 or HK1 to determine their impact on mitochondrial respiratory function by extracellular flux analysis and high-resolution respirometry.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The most effective concentration of HK3 reduced intracellular lipid content, interleukin secretion and pro-collagen 1αI levels (&lt;em&gt;p &lt;&lt;/em&gt;0.0001, &lt;em&gt;p &lt;&lt;/em&gt;0.05, &lt;em&gt;p &lt;&lt;/em&gt;0.01) in the organotypic 3D human MASH model. In hepatic stellate cells, HK3 and HK1 dose-dependently attenuated TGF-β1-induced fibrotic and inflammatory biomarker expression (&lt;em&gt;p &lt;&lt;/em&gt;0.0001) and diminished cell migration (&lt;em&gt;p &lt;&lt;/em&gt;0.0001). &lt;em&gt;In vivo&lt;/em&gt;, HK3 prevented fibrosis progression (&lt;em&gt;p &lt;&lt;/em&gt;0.05) in a carbon tetrachloride mouse model and reduced body fat mass (&lt;em&gt;p &lt;&lt;/em&gt;0.0001) in a diet-induced obesity mouse model. Accordingly, HK3 increased proton leakage and mitochondrial uncoupling efficiency in adipocytes (&lt;em&gt;p &lt;&lt;/em&gt;0.0001) and visceral adipose tissue (&lt;em&gt;p &lt;&lt;/em&gt;0.001).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;HK3 attenuates hepatic fibrosis in preclinical MASH models, while reducing body fat through adipocyte mitochondrial uncoupling. Thus, HK3 offers a promising multi-targeted first-in-class pharmacological approach for obesity-associated MASLD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Obesity-related fatty liver disease can progress to severe liver scarring, yet effective treatments targeting both liver damage and metabolic dysfunction remain rare. This study investigates HK3, a novel small molecule, which reduced liver fat, inflammation, and scarring while also lowering body fat in multiple preclinical models. These findings are particularly relevant for patients with obesity-related fatty liver disease, where current therapies often fail to adequately address fibrosis,","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 5","pages":"Article 101792"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771889","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":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(26)00153-9","DOIUrl":"10.1016/S2589-5559(26)00153-9","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 5","pages":"Article 101882"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147850619","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 immunotherapy to reduce recurrence in resectable hepatocellular carcinoma - lessons learned from the CARES-009 trial","authors":"Laia Aceituno ,&nbsp;Arndt Vogel","doi":"10.1016/j.jhepr.2026.101820","DOIUrl":"10.1016/j.jhepr.2026.101820","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 5","pages":"Article 101820"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771870","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}