JHEP Reports最新文献

{"title":"From model to man: Understanding Tregs' dual role in MASLD","authors":"Janine Dywicki ,&nbsp;Laura Elisa Buitrago-Molina ,&nbsp;Anna K. Baumann ,&nbsp;Ana C. Davalos-Misslitz ,&nbsp;Celina M. Hendriks ,&nbsp;Katharina L. Hupa-Breier ,&nbsp;Maren Lieber ,&nbsp;Jerome Schlue ,&nbsp;Matthias Blüher ,&nbsp;Heike Bantel ,&nbsp;Christine S. Falk ,&nbsp;Christian Koenecke ,&nbsp;Freya Wellhöner ,&nbsp;Benjamin Heidrich ,&nbsp;Michael P. Manns ,&nbsp;Fatih Noyan ,&nbsp;Heiner Wedemeyer ,&nbsp;Richard Taubert ,&nbsp;Elmar Jaeckel ,&nbsp;Matthias Hardtke-Wolenski","doi":"10.1016/j.jhepr.2025.101619","DOIUrl":"10.1016/j.jhepr.2025.101619","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) affects around 30% of the world's population and is often associated with metabolic conditions such as obesity, diabetes and hypertension. Approximately 10-20% of metabolic dysfunction-associated steatotic liver disease cases progress to metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the risk of liver cancer. While intrahepatic immune responses involving CD4+ and CD8+ T cells are potential therapeutic targets, their role in the pathogenesis of MASH is not fully understood. Regulatory T cells (Tregs), whose involvement has been controversial, require further investigation.</div></div><div><h3>Methods</h3><div>In this study, we investigated the impact of adaptive immunity on MASH using a high-fat/high-carbohydrate diet (HF-HCD) model in wild-type and <em>Rag2</em>-deficient C57BL/6 mice, supplemented with human liver samples.</div></div><div><h3>Results</h3><div>Our results showed that HF-HCD induced glucose intolerance and MASH, independent of adaptive immunity. Surprisingly, HF-HCD increased intrahepatic Treg numbers and the Treg/Teff ratio but did not alleviate the disease; instead, this increase correlated with greater disease severity. With progressing metabolic inflammation, an increased proportion of Tregs also expressed IL-17, which correlated with more severe liver pathology.</div></div><div><h3>Conclusions</h3><div>The observed expansion of Tregs and the resulting increase in the Treg/Teff ratio did not protect against MASH but correlated with more severe disease in both mice and humans, consistent with a pro-inflammatory shift towards IL-17-producing (T_H17-skewed) cells. These findings highlight the complex role of adaptive immunity in MASH progression and provide potential targets for future immunomodulatory therapies.</div></div><div><h3>Impact and implications</h3><div>Diet-induced steatohepatitis can develop without adaptive immunity, yet IL-17A-expressing Foxp3⁺ T regulatory cells (Tregs) and CD8⁺ T cells markedly amplify hepatocellular injury and fibrosis. By separating initiating (macrophage-driven) from amplifying (adaptive) immune signals, our study refines current pathogenic models and provides hepatologists and immunologists with stage-specific therapeutic targets. For clinicians and trial designers, the data indicate that stabilizing Tregs or selectively dampening pro-inflammatory T-cell subsets could complement metabolic interventions in metabolic dysfunction-associated steatotic liver disease/steatohepatitis, whereas indiscriminate Treg expansion might be counter-productive. Because the conclusions are drawn from a murine model, translation to humans will require validation in patient-derived tissues and non-invasive immune biomarkers.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101619"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569494","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":"Binge drinking acutely induces hepatic steatosis which is readily reversible: A real-world observational study in healthy adults","authors":"Kristoffer Kjærgaard ,&nbsp;Jeppe Mygind Yeoman ,&nbsp;Peter Lykke Eriksen ,&nbsp;Anne Catrine Daugaard Mikkelsen ,&nbsp;Emilie Eifer Møller ,&nbsp;Ann-Sophie Frees Wietz ,&nbsp;Andressa de Zawadzki ,&nbsp;Lars Christian Gormsen ,&nbsp;Sara Heebøll ,&nbsp;Hendrik Vilstrup ,&nbsp;Karen Louise Thomsen","doi":"10.1016/j.jhepr.2025.101623","DOIUrl":"10.1016/j.jhepr.2025.101623","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Binge drinking is a common pattern of alcohol intake often considered particularly harmful. However, its immediate effects on the development of hepatic steatosis and early alcohol-related liver injury are not well established. This study aimed to investigate the acute effects of binge drinking on the liver and its reversibility in healthy individuals.</div></div><div><h3>Methods</h3><div>Healthy adults were studied in a real-world setting before, the day after, and 10 days after attending a 3-day festival. The participants were alcohol abstinent 1 week prior to the first visit and between the last two visits. Each visit included liver MRI-proton density fat fraction and elastography, and blood tests. Alcohol and food intake were self-reported during the festival, and blood alcohol concentration was measured once daily.</div></div><div><h3>Results</h3><div>Fifteen participants (9 male, 6 female) aged 36 ± 5 years with a BMI of 23.2 ± 2.7 kg/m² completed the study. They consumed 186 ± 56 g of alcohol per day resulting in a 2.5-fold increase in hepatic fat fraction from 1.9% (IQR 1.6%-2.5%) to 4.6% (IQR 2.4%-5.7%), <em>p</em> &lt;0.0001. Six participants (40%) developed steatosis; compared to those without steatosis, they had higher baseline BMI, triglycerides and glucagon, and lower free fatty acids, while there was no difference in alcohol or energy consumption. Binge drinking also increased liver stiffness and triglycerides, while LDL-cholesterol decreased. After 10 days of abstinence, all outcome measures were normalised.</div></div><div><h3>Conclusions</h3><div>Three days of recreational binge drinking increased liver fat content and stiffness in most participants. This early consequence of excessive alcohol intake was resolved after 10 days of abstinence, suggesting that the acute hepatic effects of binge drinking are readily reversible if followed by short-term abstinence.</div></div><div><h3>Impact and implications</h3><div>Binge drinking is considered a high-risk pattern of alcohol intake associated with various health hazards, yet its immediate effects on the liver are not well understood. This study provides direct real-world evidence that one episode of binge drinking (3 days) can acutely induce hepatic steatosis in healthy individuals, particularly those with subclinical metabolic dysfunction. Importantly, all consequences of binge drinking were normalised following 10 days of alcohol abstinence. These findings offer timely insight into the health risks of recreational binge drinking and contribute knowledge with potential implications for public health messaging and recommendations, clinical guidance, and alcohol policies.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101623"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594694","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":"Epidemiology, clinical, molecular features, and prognosis of early-onset biliary tract cancer: A systematic review and meta-analysis","authors":"Erman Akkus ,&nbsp;Antonella Cammarota ,&nbsp;Laura Izquierdo-Sanchez ,&nbsp;Jesus M. Banales ,&nbsp;Alejandro Forner ,&nbsp;Ana Lleo ,&nbsp;Rocio I.R. Macias ,&nbsp;Angela Lamarca ,&nbsp;Mohamed Bouattour","doi":"10.1016/j.jhepr.2025.101613","DOIUrl":"10.1016/j.jhepr.2025.101613","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Early-onset gastrointestinal cancers represent a growing global health concern. Among these, early-onset biliary tract cancer (EO-BTC) remains relatively understudied. In this systematic review, we synthesize current evidence for EO-BTC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A comprehensive systematic literature search was performed across multiple databases. Original studies investigating epidemiology, risk factors, clinical presentation, pathological and/or molecular features, treatment, and prognosis of EO-BTC were included and synthesized. Meta-analyses were performed using the Mantel–Haenszel and generic inverse variance methods with random-effects models.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In total, 32 studies were included. EO-BTC incidence varied by anatomical subtype, with a notable increase in early-onset intrahepatic cholangiocarcinoma. Disparities in ethnicity and socioeconomic status were apparent between younger and older patients. Clinically, the disease was often diagnosed at a more advanced stage in younger patients (for stage IV, odds ratio [OR], 1.31; 95% CI, 1.19–1.43; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 62%) and was associated with a higher prevalence of intrahepatic cholangiocarcinoma (OR, 1.41; 95% CI, 1.23–1.61; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 49%). &lt;em&gt;FGFR2&lt;/em&gt; fusions were significantly more common in early-onset cases (OR, 2.81; 95% CI, 2.31–3.64; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 0%). Younger patients had fewer comorbidities and more frequently received curative-intent local and systemic therapies (surgery: OR, 1.38; 95% CI, 1.22–1.57; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 85%). Prognostic data were heterogeneous; however, pooled analysis suggested a trend to improved OS in patients with early-onset disease (unadjusted hazard ratio [HR], 0.84; 95% CI, 0.75–0.93; &lt;em&gt;p&lt;/em&gt; = 0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 81%); adjusted HR, 0.78; 95% CI, 0.66–0.94; &lt;em&gt;p&lt;/em&gt; = 0.007; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 91%).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;EO-BTC represents a clinically and molecularly distinct subset within biliary tract cancers, with emerging epidemiological patterns, a higher prevalence of actionable molecular alterations, and differences in treatment allocation. Further prospective and age-stratified studies are needed to guide age-adapted detection and therapeutic strategies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;PROSPERO ID&lt;/h3&gt;&lt;div&gt;CRD420251039039.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;This systematic review highlights that EO-BTC exhibits different epidemiological and molecular patterns compared with later-onset disease, including a higher prevalence of intrahepatic subtypes and greater frequency of targetable alterations, such as &lt;em&gt;FGFR2&lt;/em&gt; fusions. These findings underscore the importance of incorporating routine molecular profiling and the integration of stratified manag","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101613"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682307","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":"Comparative effectiveness of antidiabetic therapies on hepatic decompensation in patients with type 2 diabetes: A target trial emulation","authors":"Jonggi Choi ,&nbsp;Ana Verma ,&nbsp;Vy H. Nguyen ,&nbsp;Eric Przybyszewski ,&nbsp;Jiunn Song ,&nbsp;Allison Carroll ,&nbsp;Megan Michta ,&nbsp;Erik Almazan ,&nbsp;Tracey G. Simon ,&nbsp;Raymond T. Chung","doi":"10.1016/j.jhepr.2025.101624","DOIUrl":"10.1016/j.jhepr.2025.101624","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;The comparative effectiveness of antidiabetic therapies on hepatic outcomes in patients with type 2 diabetes mellitus (T2DM) is not well established.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a retrospective new-user cohort study emulating a target trial using electronic health records from the Mass General Brigham health system (USA) between January 2012 and June 2024. Adults with T2DM who newly initiated sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), or sulfonylureas were included. Propensity scores were estimated using prespecified clinical and high-dimensional covariates, and overlap weighting was applied to achieve covariate balance.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Among 38,524 eligible patients, 12,344 initiated GLP-1RAs, 5,233 SGLT2is, 3,717 DPP4is, and 17,230 sulfonylureas. Over a median follow-up of 3.1 years, 1,743 hepatic decompensation events occurred. In the intention-to-treat analysis, GLP-1RAs (hazard ratio [HR] 0.58, 95% CI 0.38–0.88) and SGLT2is (HR 0.65, 95% CI 0.43–0.98) were associated with significantly lower risk compared with sulfonylureas. Pairwise analyses also showed reduced risk with GLP-1RAs (HR 0.59, 95% CI 0.39–0.89) and SGLT2is (HR 0.66, 95% CI 0.43–1.00) compared with DPP4is, with no significant difference between GLP-1RAs and SGLT2is. In the per-protocol analysis (1,151 events), GLP-1RAs (HR 0.43, 95% CI 0.22–0.82) remained strongly protective, while SGLT2is showed a trend toward reduced risk (HR 0.61, 95% CI 0.33–1.12). Sensitivity analyses excluding early events or using alternative weighting approaches produced consistent results.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;In patients with T2DM, initiation of GLP-1RAs or SGLT2is was associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and DPP4is. These findings support their preferential use in clinical practice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;This study provides robust real-world evidence on the comparative effectiveness of four major antidiabetic drug classes in reducing hepatic decompensation among patients with type 2 diabetes mellitus. Our findings suggest that glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors, supporting their preferential use in patients with coexisting diabetes and liver disease risk. These results are particularly relevant for clinicians managing patients with type 2 diabetes who may have unrecognized metabolic dysfunction-associated steatotic liver disease or other chronic liver diseases. In practice, these findings can help guide therapeutic decision-making by integrating liver-related outcomes into antidiabetic drug selection. However, future pros","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101624"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569427","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":"Liver fibrosis is associated with clinical and economic burden of cardiovascular disease in MASH","authors":"Kathleen Corey ,&nbsp;Anurag Mehta ,&nbsp;Kamal Kant Mangla ,&nbsp;Abhishek Shankar Chandramouli ,&nbsp;Ahsan Shoeb ,&nbsp;Niels Krarup ,&nbsp;Margarida Augusto ,&nbsp;Katrine Grau ,&nbsp;Sharat Varma ,&nbsp;Elisabetta Bugianesi","doi":"10.1016/j.jhepr.2025.101621","DOIUrl":"10.1016/j.jhepr.2025.101621","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The clinical and economic burden of cardiovascular (CV) disease (CVD) in patients with metabolic dysfunction-associated steatohepatitis (MASH) is incompletely understood. The unCoVer–MASH cohort study aimed to assess the association of CVD-related burden with fibrosis (Fibrosis-4 index [FIB-4]) in patients with MASH in a real-world US database.</div></div><div><h3>Methods</h3><div>Adult patients with an ICD code for non-alcoholic steatohepatitis (NASH; October 2015–June 2022) were included if they had ≥1 FIB-4 measurement calculated from data obtained within 180 days before or 30 days after the NASH diagnosis (index date), ≥12 months of data prior to the index date (baseline period), and no diagnostic evidence of cirrhosis at baseline. FIB-4 categories were low (&lt;1.30), intermediate (1.30–2.67), and high (&gt;2.67). Risk of CV events was assessed during follow-up, and hazard ratios (HRs) were calculated using Cox proportional hazards models. CVD-related economic burden and resource utilization were also assessed.</div></div><div><h3>Results</h3><div>Of 715 patients included at baseline,102 had high, 201 had intermediate, and 412 had low FIB-4 scores. The risk of any CV event was significantly greater in the high (HR 3.44; 95% CI 2.22–5.34; <em>p</em> &lt;0.001) and intermediate (HR 1.53; 95% CI 1.02–2.31; <em>p</em> = 0.040) FIB-4 groups compared with the low group. The risk remained significant after adjustment for CV risk factors in patients with high <em>vs</em>. low FIB-4 (HR 2.026; 95% CI 1.215–3.380; <em>p</em> = 0.007). Additionally, CV-related healthcare resource utilization and CV-related costs increased with higher FIB-4 scores.</div></div><div><h3>Conclusions</h3><div>Patients with MASH and high baseline FIB-4 scores were at an increased risk of CV events and had higher CV-related healthcare costs and resource utilization.</div></div><div><h3>Impact and implications</h3><div>Studies specifically evaluating the clinical and economic burden of CVD in patients with MASH, without diagnostic evidence of cirrhosis, are lacking. In the current study, the clinical and economic burden of CVD in such patients was associated with baseline liver fibrosis severity, as assessed using baseline FIB-4 score, indicating a higher CV burden among patients with higher fibrosis severity. These results are important for both clinicians and payers, as they illustrate that tackling the CV-related burden in MASH is likely to have an appreciable impact on both clinical and economic outcomes.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101621"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682306","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":"Transcriptome of monocytes from liver, brain and bone marrow reveals organ-specific features in aging and alcohol misuse","authors":"Martí Ortega-Ribera ,&nbsp;Radhika Joshi ,&nbsp;Sergi Guixé-Muntet ,&nbsp;Veronika Brezani ,&nbsp;Prashanth Thevkar Nagesh ,&nbsp;Viliam Brezani ,&nbsp;Arman Patel ,&nbsp;Yuan Zhuang ,&nbsp;Mrigya Babuta ,&nbsp;Jordi Gracia-Sancho ,&nbsp;Gyongyi Szabo","doi":"10.1016/j.jhepr.2025.101603","DOIUrl":"10.1016/j.jhepr.2025.101603","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear.</div></div><div><h3>Methods</h3><div>We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20–24-month-old) female C57BL/6N mice (n = 4–6 per group). Statistical significance was determined using two-way ANOVA.</div></div><div><h3>Results</h3><div>MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways.</div></div><div><h3>Conclusion</h3><div>Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse.</div></div><div><h3>Impact and implications</h3><div>Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101603"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569491","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":"Viral sequence analysis of chronic hepatitis B patients treated with the siRNA JNJ-73763989 in phase II clinical trials","authors":"Thierry Verbinnen ,&nbsp;Erkki Lathouwers ,&nbsp;John Jezorwski ,&nbsp;Michael Biermer ,&nbsp;Ilse Augustyns ,&nbsp;Craig Grant ,&nbsp;Kosh Agarwal ,&nbsp;Man-Fung Yuen ,&nbsp;Sandra De Meyer ,&nbsp;Oliver Lenz","doi":"10.1016/j.jhepr.2025.101618","DOIUrl":"10.1016/j.jhepr.2025.101618","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;JNJ-73763989 (JNJ-3989) is a small-interfering RNA composed of two triggers targeting the HBsAg and HBx protein open reading frame, designed to target all HBV RNAs for degradation. JNJ-3989 + nucleos(t)ide analogue (NA) treatment dose-dependently reduced chronic hepatitis B (CHB) viral antigens. Viral sequence changes in the JNJ-3989 S-/X-trigger target regions were evaluated at baseline, on-treatment, and in patients with virologic relapse (VR) after discontinuation of all treatment in REEF-1 (NCT03982186) and REEF-2 (NCT0412954) studies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;HBV DNA/RNA was extracted from plasma samples, and the HBV genome was sequenced using next-generation sequencing. Nucleotide variants were defined as changes &lt;em&gt;vs.&lt;/em&gt; the universal HBV reference sequence (read frequency &gt;15%).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Baseline polymorphisms in the JNJ-3989 target region complementary to positions 2-18 of the S-/X-trigger were present in 10.1% and 2.4% of not currently treated patients, respectively, with no relevant impact on JNJ-3989-induced HBsAg decline. Variants at X-trigger target region positions of interest (POI) were more frequently observed off treatment in JNJ-3989-treated virologically suppressed (VS) patients with VR &lt;em&gt;vs&lt;/em&gt;. NA-control arm VS patients with VR (55.8% &lt;em&gt;vs&lt;/em&gt;. 5.7%, respectively). Variants at S-trigger POI were observed off treatment in 32.1% and 19.4% of JNJ-3989- and NA-control treated VS patients with VR, respectively. Off-treatment HBsAg kinetics did not differ between JNJ-3989-treated patients with and without variants in S-/X-trigger target POI during VR.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Baseline sequence polymorphisms did not impact JNJ-3989 treatment response. JNJ-3989-treated patients who experienced VR post-treatment had variants in the X-trigger target region during VR, but not at baseline or on-treatment, suggesting that X-trigger variants developed off treatment in JNJ-3989-treated patients. The presence of these variants did not impact off-treatment HBsAg kinetics.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;ClinicalTrial.gov Identifiers&lt;/h3&gt;&lt;div&gt;NCT03982186 and NCT0412954.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Small-interfering RNA (siRNA) therapy with JNJ-3989 in patients with chronic hepatitis B induces potent, dose-dependent reductions in viral antigens, though the magnitude of decline varies among individuals. Baseline nucleotide polymorphisms in JNJ-3989 trigger target regions did not account for variability in HBsAg or HBeAg responses. Substitutions in siRNA trigger target regions were frequently detected during and after virologic relapse in JNJ-3989-treated patients, confirming antiviral target engagement. However, the emergence of these variants did not affect off-treatment HBsAg or HBV DNA kinetics. This study provides the first comprehensive clinical virology analysis of siRNA-based therapy in HBV infection, offering insight","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101618"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569425","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":"HBV X protein regulates cancer stemness and tumor invasiveness through SENP1 in hepatocellular carcinoma","authors":"Yu-Chih Wu ,&nbsp;Yen-Chiao Huang ,&nbsp;Yung-Che Kuo ,&nbsp;Mai-Huong Thi Ngo ,&nbsp;Kam-Fai Lee ,&nbsp;Yen-Tseng Sung ,&nbsp;Hsiao-Feng Wang ,&nbsp;Shin-Lian Doong ,&nbsp;Liang-Mou Kuo ,&nbsp;Te-Sheng Chang ,&nbsp;Yen-Hua Huang","doi":"10.1016/j.jhepr.2025.101620","DOIUrl":"10.1016/j.jhepr.2025.101620","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The niche in hepatocellular carcinoma (HCC) critically influences cancer stem cell (CSC)-associated properties, including stemness, early recurrence, and poor prognoses. HBV infection acts as a niche driver for tumor progression and malignancy. While the HBV X (HBx) protein has been linked to CSC-associated properties, the underlying molecular mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>Paired tumor and peritumor tissues from 211 patients with HCC were analyzed to correlate <em>SENP1</em>, <em>OCT4</em>, <em>SNAIL</em>, <em>PIN1</em>, and <em>TWIST</em> expression with overall survival (OS) and disease-free survival (DFS) using a Kaplan-Meier survival analysis. Validation was performed using HCC microarray data (n = 167). HBx-SENP1’s role in regulating CSC-associated properties was examined <em>in vitro</em> (stemness expression, sphere formation, CD133⁺ cells, migration/invasion, and sorafenib sensitivity) and <em>in vivo</em> using an orthotopic xenograft model.</div></div><div><h3>Results</h3><div>Clinically, SENP1 expression was correlated with OCT4, SNAIL, and TWIST (<em>p &lt;</em>0.001), and was associated with poor OS (69.2 <em>vs.</em> 172.8 months, <em>p</em> &lt;0.001) and DFS (15.8 <em>vs.</em> 39.7 months, <em>p &lt;</em>0.001). SENP1 expression was correlated with gene sets linked to HCC recurrence and embryonic stem cell signatures. In HBV-related HCC, elevated SENP1 (7.8 <em>vs.</em> 15.7 months, <em>p</em> = 0.003), OCT4 (7.8 <em>vs.</em> 16.7 months, <em>p</em> &lt;0.001), SNAIL (8.6 <em>vs.</em> 15.7 months, <em>p</em> = 0.012), and TWIST (8.2 <em>vs.</em> 15.5 months, <em>p</em> = 0.028) were linked to early recurrence. Mechanistically, HBx induced CSC-associated properties through SENP1, including sphere formation, CD133⁺ cells, migration/invasion, and sorafenib resistance. SENP1-knockdown decreased HBx-induced pulmonary metastases and sorafenib refractoriness <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>HBx-induced SENP1 is critical for CSC properties. SENP1 can serve as a novel biomarker for early recurrence, metastasis, and drug resistance, particularly in HBV-related HCC.</div></div><div><h3>Impact and implications</h3><div>Early recurrence, tumor metastasis, and drug resistance are significant therapeutic challenges in hepatocellular carcinoma (HCC), which are closely associated with cancer stem cell (CSC)-related properties. In this study, we demonstrated that HBx-induced SENP1 expression regulates CSC-related properties and tumor metastasis, particularly in HBV-related HCC, in clinical, <em>in vitro</em>, and <em>in vivo</em> settings. Findings from this research highlight that HBx-induced SENP1 is crucial for promoting CSC-associated properties in HCC. SENP1 could serve as a novel biomarker of early tumor recurrence and metastasis, especially for HBV-related HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101620"},"PeriodicalIF":7.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682323","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":"Enhanced nuclear localization of small heterodimer partner in metabolic dysfunction-associated steatohepatitis","authors":"Shih-Chieh Chien ,&nbsp;Chiung-Yu Chen ,&nbsp;Hung-Wen Tsai ,&nbsp;Yih-Jyh Lin ,&nbsp;Shu-Chu Shiesh ,&nbsp;Pin-Nan Cheng ,&nbsp;Hung-Chih Chiu ,&nbsp;Yen-Cheng Chiu ,&nbsp;Ya-Han Lin ,&nbsp;Min-Shan Wu ,&nbsp;Mei-Juan Zheng ,&nbsp;Kung-Chia Young ,&nbsp;Yau-Sheng Tsai","doi":"10.1016/j.jhepr.2025.101616","DOIUrl":"10.1016/j.jhepr.2025.101616","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The nuclear factor small heterodimer partner (SHP) plays a dual function in maintaining bile acid (BA) homeostasis and exerting anti-inflammatory effects. While SHP might be associated with metabolic dysfunction-associated steatohepatitis (MASH), its role in patients remains unclear.</div></div><div><h3>Methods</h3><div>Liver tissue and serum samples were collected from 69 patients with MASH and 10 healthy controls. The subcellular distribution of SHP and related proteins in liver tissue were analyzed to correlate with MASH-associated pathological characteristics. <em>In vitro</em> studies were conducted to elucidate the underlying mechanisms and clinical relevance of SHP nuclear translocation in MASH.</div></div><div><h3>Results</h3><div>Compared with controls, patients with MASH demonstrated a higher nuclear SHP ratio (51.7% <em>vs.</em> 1.55%, <em>p</em> &lt;0.001), which correlated with the severity of hepatitis and steatosis, but not with serum BA levels. The nuclear SHP ratio increased in parallel with atypical protein kinase C zeta (PKCζ) signal intensity and showed high co-localization with nucleoporin RanBP2. <em>In vitro</em> experiments demonstrated that both toxic fatty acid and inflammatory cytokine could induce SHP nuclear translocation, which was blocked by PKCζ inhibition. <em>SHP</em> knockdown increased basal innate immune activity, accelerated intracellular lipid accumulation, and recapitulated a MASH-like gene profile that facilitates BA accumulation.</div></div><div><h3>Conclusions</h3><div>Nuclear SHP accumulation is a distinctive feature of MASH pathology. This PKCζ-dependent process may exert anti-inflammation and anti-cholestasis function in patients with MASH.</div></div><div><h3>Impact and implications</h3><div>The nuclear factor small heterodimer partner (SHP) plays a dual role in maintaining bile acid homeostasis and suppressing inflammation. In patients with metabolic dysfunction-associated steatohepatitis (MASH), we identified a pathological increase in the hepatocellular nuclear SHP ratio, likely triggered by lipid overload and inflammatory stimuli, and dependent on PKCζ activation. <em>SHP</em> knockdown <em>in vitro</em> induced cellular steatosis, innate immune responses, and leading to a cholestatic gene expression profile. These findings highlight SHP as a potential therapeutic target in MASH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101616"},"PeriodicalIF":7.5,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682290","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":"3D endothelial cell scaffolds protect liver explants and exhibit therapeutic effects on liver fibrosis","authors":"Mireia Medrano-Bosch ,&nbsp;Alazne Moreno-Lanceta ,&nbsp;Blanca Simón-Codina ,&nbsp;David Saavedra-Pérez ,&nbsp;Yiliam Fundora ,&nbsp;Francisco J. Sánchez ,&nbsp;Meritxell Perramón ,&nbsp;Laura Macias-Muñoz ,&nbsp;Manuel Morales-Ruiz ,&nbsp;Elazer R. Edelman ,&nbsp;Wladimiro Jiménez ,&nbsp;Pedro Melgar-Lesmes","doi":"10.1016/j.jhepr.2025.101617","DOIUrl":"10.1016/j.jhepr.2025.101617","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Endothelial cells (ECs) display myriad protective roles that support tissue homeostasis. Embedding healthy ECs in 3D scaffolds stabilizes their phenotype to maximize reparative effects and shields immunogenicity. Here, we evaluate the protective effects of matrix-embedded ECs (MEECs) in liver explants and models of chronic liver disease.</div></div><div><h3>Methods</h3><div>Precision cut liver slices (PCLS) from patients with cirrhosis (n = 8) and fibrotic or healthy mice (n = 6) were co-cultured with MEECs for 24 h and hepatic viability and inflammation were analyzed. The protective effects of the MEECs secretome were explored <em>in vitro</em>. MEECs were perihepatically or subcutaneously implanted for 1 week in fibrotic mice with or without hepatectomy (n = 6) to evaluate their effects on liver inflammation, regeneration, and fibrosis.</div></div><div><h3>Results</h3><div>MEECs protected liver viability in PCLS from patients with cirrhosis (ATP/protein, 2.7 <em>vs.</em> 5.0, <em>p</em> = 0.01) and fibrotic (5.3 <em>vs.</em> 7.1, <em>p</em> = 0.01) or healthy (7.8 <em>vs.</em> 10.6, <em>p</em> = 0.01) mice, and reduced injury-induced inflammation. MEECs produced hepatocyte growth factor and fibroblast growth factor 2, which were associated with improved hepatic viability and anti-inflammatory macrophage polarization, respectively. Perihepatic implantation of MEECs in fibrotic mice with or without hepatectomy reduced inflammation and hepatic damage and exhibited pro-regenerative and antifibrotic properties (Sirius red⁺ area, 8.3 <em>vs.</em> 6.4, <em>p</em> = 0.005). These antifibrotic effects were associated with higher production of heparan sulfate and metalloproteinases 2 and 9, and mitigation of hepatic stellate cell activation. Implantation of MEECs at a distance from the liver did not reduce liver injury, inflammation, or fibrosis.</div></div><div><h3>Conclusions</h3><div>Endothelial–hepatocyte regulation is essential in liver repair, and matrix-embedded endothelial cells (MEECs) appear to be a potential therapy for chronic liver injury and <em>ex situ</em> preservation of liver grafts.</div></div><div><h3>Impact and implications</h3><div>Organ transplantation is the most effective therapy for advanced liver disease, yet remains limited by preservation of harvested graft viability and injury-induced inflammation post implantation. Healthy ECs display myriad protective roles that contribute to tissue homeostasis. In this study, we show how MEECs preserve cell viability and reduce inflammation in hepatic explants and display anti-inflammatory, antifibrotic and pro-regenerative properties in the liver of fibrotic mice. These dynamic and unique hepatoprotective properties of MEECs highlight their potential therapeutic utility for chronic liver injury or <em>ex situ</em> conservation of liver grafts.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101617"},"PeriodicalIF":7.5,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682286","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}