JHEP Reports最新文献

{"title":"C/EBPβ–VCAM1 axis in Kupffer cells promotes hepatic inflammation in MASLD","authors":"Shuang-Zhe Lin ,&nbsp;Yang Xie ,&nbsp;Yu-Qing Cheng ,&nbsp;Rui Xue ,&nbsp;Yin-Shi Su ,&nbsp;Mingxi Liu ,&nbsp;Yuan-Wen Chen ,&nbsp;Jian-Gao Fan","doi":"10.1016/j.jhepr.2025.101418","DOIUrl":"10.1016/j.jhepr.2025.101418","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Kupffer cells (KCs) can promote hepatic inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying molecular mechanisms are not fully understood. C/EBPβ in macrophages can mediate metabolic and immune dysregulations. Therefore, we aimed to explore its role in KCs in MASLD pathogenesis.</div></div><div><h3>Methods</h3><div>A 12-week high-fat and high-cholesterol diet (HFHCD) model was used in wild-type or KC-specific <em>Cebpb</em> heterozygous knockout mice (n = 10 per group), followed by liver evaluation using histopathology, flow cytometry, and RNA-seq. RNA-seq of liver tissue (n = 3 per group) and C/EBPβ CUT&amp;Tag-seq of sorted KCs were comprehensively analyzed to elucidate the transcriptional regulatory network. Flow cytometry and immunofluorescence were used to detect the expression or distribution of key proteins.</div></div><div><h3>Results</h3><div>HFHCD induced prominent immune cell infiltration and a concomitant increase in C/EBPβ in KCs. KC-specific <em>Cebpb</em> heterozygous knockout significantly reduced HFHCD-induced lobular inflammation (<em>p</em> &lt;0.05) and inflammation-related gene expression (<em>p</em> &lt;0.05) in the liver. Multi-omics analysis revealed increased C/EBPβ activity in KCs in MASLD, leading to a selective promotive effect on MASLD-induced genes. Further integrated analysis identified <em>Vcam1</em> as a key direct downstream gene of C/EBPβ in KCs in MASLD, which involves C/EBPβ-mediated activation of the <em>Vcam1</em> promoter. VCAM1 was predominantly expressed in KCs in the hepatic tissue of MASLD mice and patients. KC-expressed VCAM1 was significantly increased in MASLD compared with healthy controls (<em>p</em> &lt;0.01), and it promoted immune cell infiltration into the liver.</div></div><div><h3>Conclusions</h3><div>Increased C/EBPβ in KCs promotes pathogenic transcriptional activation, leading to increased VCAM1 expression and inflammatory cell infiltration in MASLD. Inhibition of C/EBPβ in KCs might be a potential therapeutic strategy against hepatic inflammation in MASLD.</div></div><div><h3>Impact and implications</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathogenesis remains elusive. In this study, we investigated the critical role of CCAAT/enhancer binding protein β (C/EBPβ) in Kupffer cells and its implications in MASLD pathogenesis. We found that an increased C/EBPβ level in Kupffer cells promotes hepatic inflammation in MASLD by upregulating VCAM1 expression. Our findings provide valuable insights into the molecular mechanisms driving MASLD and propose a potential novel therapeutic target to mitigate hepatic inflammation in MASLD.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101418"},"PeriodicalIF":9.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535965","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":"The association between childhood obesity and major adverse liver outcomes in adolescence and young adulthood","authors":"Resthie R. Putri ,&nbsp;Thomas Casswall ,&nbsp;Pernilla Danielsson ,&nbsp;Claude Marcus ,&nbsp;Emilia Hagman","doi":"10.1016/j.jhepr.2025.101425","DOIUrl":"10.1016/j.jhepr.2025.101425","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Paediatric obesity is associated with liver steatosis and injury. We aimed to investigate the association between paediatric obesity and the risk of major adverse liver outcomes (MALOs) during adolescence and adulthood.</div></div><div><h3>Methods</h3><div>A cohort study of children with overweight or obesity enrolled in the Swedish Childhood Obesity Treatment Register (1997–2020) was performed (n = 29,321). Controls from the general population matched by sex, birth year, and resident areas were obtained (n = 141,510). The individuals were followed from age 10 (or obesity treatment initiation) up to age 40. MALOs were defined as any occurrence of cirrhosis, hepatocellular carcinoma, oesophageal or gastric varices, portal hypertension, liver transplantation, ascites, liver failure, or liver-related mortality.</div></div><div><h3>Results</h3><div>During a median follow-up of 8.3 [Q1–Q3: 5.5–11.8] years, MALOs were identified in 77 individuals. The cumulative incidence of MALOs by age 40 was 1.14% in the obesity cohort and 0.52% in the control group. Childhood adiposity was associated with the risk of MALOs (hazard ratio 2.15, 95% CI 1.33–3.48, <em>p =</em> 0.002). Individuals who had childhood obesity and developed alcohol use disorder during follow-up had an even higher risk of MALOs than controls without alcohol use disorder (hazard ratio 7.64, 95% CI 2.73–21.47, <em>p</em> &lt;0.001). Type 2 diabetes did not mediate the association between childhood obesity and MALOs (<em>p =</em> 0.54).</div></div><div><h3>Conclusions</h3><div>Paediatric obesity is associated with a two-fold increased risk of MALOs. However, the absolute risk of developing MALOs by age 40 remains low.</div></div><div><h3>Impact and implications</h3><div>Firstly, healthcare providers should recognise that the consequences of paediatric obesity are not limited to immediate health concerns but rather present a sustained consequence on liver health into adulthood. Secondly, our findings revealed that a substantial proportion of individuals with alcohol use disorder experienced onset during adolescence, significantly amplifying the risk of major adverse liver outcomes. This underscores the importance of incorporating routine assessment for alcohol use disorder within paediatric care, particularly during adolescence, to identify and mitigate this increased risk. Thirdly, while the incidence of major adverse liver outcomes up to age 40 remains low, we identify a population at increased risk. This could help to refine risk stratification and target interventions more effectively.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 7","pages":"Article 101425"},"PeriodicalIF":9.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279214","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":"Temporal dichotomy of neutrophil function in acute liver injury and repair","authors":"Jennifer A. Cartwright ,&nbsp;Philippe M.D. Potey ,&nbsp;Eilidh Livingstone ,&nbsp;Lara Campana ,&nbsp;Philip J. Starkey Lewis ,&nbsp;Magdalena E.M. Oremek ,&nbsp;Naomi N. Gachanja ,&nbsp;Giulia Rinaldi ,&nbsp;Rhona E. Aird ,&nbsp;Tak Yung Man ,&nbsp;Anuruddika J. Fernando ,&nbsp;Joanna P. Simpson ,&nbsp;Natalie Z.M. Homer ,&nbsp;Nicole Barth ,&nbsp;Melisande Addison ,&nbsp;Candice Ashmore-Harris ,&nbsp;Maria Elena Candela ,&nbsp;Alastair M. Kilpatrick ,&nbsp;Matthieu Vermeren ,&nbsp;Calum T. Robb ,&nbsp;Adriano G. Rossi","doi":"10.1016/j.jhepr.2025.101417","DOIUrl":"10.1016/j.jhepr.2025.101417","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; aims&lt;/h3&gt;&lt;div&gt;Acetaminophen (APAP)-induced acute liver injury (APAP-ALI) is the leading cause of acute liver failure-induced death, with host innate immune responses driving outcomes. Neutrophils are activated and increased in APAP-ALI and reported to contribute to liver damage. However, neutrophil dysfunction in patients with acute liver failure is associated with non-survival, and recent reports highlight their importance in hepatic repair. Neutrophil-targeted therapies for APAP-ALI are hampered by this controversy and a lack of time-dependent investigation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Hepatic neutrophils were depleted at different times in a wild-type mouse model of APAP-ALI. &lt;em&gt;Fpr1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; mice, with reduced neutrophil activation, were also used. The impact of neutrophil depletion was interrogated during hepatic injury and repair after APAP-ALI, using serum biochemistry, liver and blood flow cytometry, liver histopathology, immunohistochemistry, ELISA, and NanoString analysis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Neutrophils contributed both to hepatic damage and repair after APAP-ALI. Early liver necrosis was reduced by neutrophil depletion (34% to 23%, &lt;em&gt;p&lt;/em&gt; = 0.0018, n ≥10) and by reducing neutrophil functions (39% to 29%, &lt;em&gt;p&lt;/em&gt; = 0.0279, n ≥11). By contrast, late neutrophil depletion resulted in markedly reduced liver repair (persistent necrosis 17% to 30%, &lt;em&gt;p&lt;/em&gt; = 0.016, and higher serum alanine aminotransferase [1,221 to 3,725 IU/l, &lt;em&gt;p&lt;/em&gt; = 0.0007, n ≥10]) and hepatocyte proliferation (decreased minichromosomal maintenance 2+ hepatocytes, 3% to 1%, &lt;em&gt;p&lt;/em&gt; = 0.025, n = 10). Late neutrophil depletion reduced proliferation, growth factors, and angiogenesis transcripts (Mik6 fold change [FC] -6.322, &lt;em&gt;p&lt;/em&gt; = 0.002; Socs2 FC -2.91, &lt;em&gt;p&lt;/em&gt; = 0.01; vascular endothelial growth factor A FC -1.48, &lt;em&gt;p&lt;/em&gt; = 0.01; n = 3). Similar transcript changes were identified when preventing formylated peptide receptor 1-mediated neutrophil activation, along with reduced extracellular matrix remodeling (Col12a1, FC -1.99, &lt;em&gt;p&lt;/em&gt; = 0.0001; n ≥5). Finally, depleting neutrophils resulted in a hepatic proinflammatory monocyte/macrophage phenotype during repair stages, with increased proinflammatory-related transcripts and reduced reparative transcripts.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Recruited neutrophils contribute not only to hepatic damage early in APAP-ALI, but also to hepatic repair through a variety of pathways, including extracellular matrix remodeling, angiogenesis, hepatocyte proliferation, and promotion of an anti-inflammatory monocyte/macrophage phenotype.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Novel therapies are required for APAP-ALI to improve patient outcomes. Neutrophil products and functions are potential targets for future therapies, but current literature controversy and a lack of time-dependent studies hinder progression. This","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 7","pages":"Article 101417"},"PeriodicalIF":9.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307750","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":"Regional variations and trends in liver transplantation practices across Europe","authors":"Tommaso Di Maira ,&nbsp;Valérie Cailliez ,&nbsp;Beatriz Domínguez-Gil ,&nbsp;Beatriz Mahíllo ,&nbsp;Marina Álvarez ,&nbsp;Luca Saverio Belli ,&nbsp;René Adam ,&nbsp;Constantino Fondevila ,&nbsp;Giacomo Germani ,&nbsp;Hermien Hartog ,&nbsp;Marina Berenguer ,&nbsp;European Liver and Intestine Transplant Association (ELITA)","doi":"10.1016/j.jhepr.2025.101424","DOIUrl":"10.1016/j.jhepr.2025.101424","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Liver transplantation (LT) is a live-saving therapy for patients with end-stage liver disease, but demand exceeds supply, leading to waiting list (WL) mortality. This study reviews LT practices and trends in Europe to identify potential policies for improving outcomes.</div></div><div><h3>Methods</h3><div>Data were extracted from the European Liver Transplant Registry and the Global Observatory on Donation and Transplantation. Countries were categorized into Eastern (EEC), Mediterranean (MEC), and Northern European (NEC). We analyzed LT indications, recipient and donor age, transplant type, and WL outcomes from 2012 to 2022.</div></div><div><h3>Results</h3><div>Etiology of LT differed across regions: HBV cirrhosis predominated in EEC (37.3%), whereas alcohol-related liver disease was more frequent in NEC (41.8%) and MEC (49.1%). Metabolic-dysfunction associated steatotic liver disease increased across Europe, particularly in NEC. Recipient age has risen, with 40% aged ≥60 years in MEC <em>vs.</em> 20% in EEC. Donor age and type also varied: EEC relies on younger donors (&lt;50 years, 70%), whereas MEC expanded criteria to include donors ≥60 years (50%). Donation after circulatory determination of death increased by 30%, particularly in NEC and MEC, but remains rare in EEC. Model for end-stage liver disease scores at LT decreased, with 30% scoring &gt;21 in 2021 <em>vs.</em> 50% in 2012. WL mortality declined by 10% since 2015, although large inter-country variability persists.</div></div><div><h3>Conclusions</h3><div>LT practices in Europe are highly heterogeneous. Regional disparities in recipient profiles, donor characteristics, and transplant modalities reflect varying policies and healthcare capacities. Expanding donor criteria and harmonizing allocation systems are required to reduce WL mortality and improve access to LT across Europe.</div></div><div><h3>Impact and implications</h3><div>This study provides a comprehensive analysis of liver transplantation practices across Europe, highlighting significant regional disparities in donor criteria, allocation systems, and transplant outcomes. By identifying trends such as the expansion of Donation after Circulatory Determination of Death programs and the prioritization of model for end-stage liver disease ≥30 policies, these findings underscore the critical need for harmonized strategies to reduce waiting list mortality and improve access to transplantation. The results are particularly relevant for policymakers and healthcare administrators seeking to optimize liver transplant systems, and for clinicians aiming to adopt best practices from high-performing regions. Practical applications include refining allocation policies, expanding donor pools, and addressing regional inequalities, all while considering the limitations posed by diverse healthcare infrastructures and socioeconomic factors.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101424"},"PeriodicalIF":9.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597301","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":"ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling","authors":"Yujia Li ,&nbsp;Chenjun Huang ,&nbsp;Weiguo Fan ,&nbsp;Seddik Hammad ,&nbsp;Cyrill Géraud ,&nbsp;Lea Berger ,&nbsp;Shanshan Wang ,&nbsp;Ye Yao ,&nbsp;Chenhao Tong ,&nbsp;Claudia Rubie ,&nbsp;Laura Kim Feiner ,&nbsp;Zeribe C. Nwosu ,&nbsp;Frederik Link ,&nbsp;Pia Erdösi ,&nbsp;Weronika Piorońska ,&nbsp;Kerry Gould ,&nbsp;Christoph Meyer ,&nbsp;Rilu Feng ,&nbsp;Hui Liu ,&nbsp;Chen Shao ,&nbsp;Sai Wang","doi":"10.1016/j.jhepr.2025.101423","DOIUrl":"10.1016/j.jhepr.2025.101423","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-beta quiescent. Upon hepatocyte damage, ECM1 is significantly downregulated, facilitating fibrosis and chronic liver disease (CLD) progression. We investigated the mechanism of ECM1 regulation in hepatocytes under pathophysiological conditions.</div></div><div><h3>Methods</h3><div>We used promoter analysis to predict <em>Ecm1</em> transcriptional regulators and assessed the expression of <em>Ecm1</em>-related genes by single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. Functional assays were performed with AML12 cells, mouse and human primary hepatocytes, and liver tissue from mice and patients.</div></div><div><h3>Results</h3><div>In healthy hepatocytes, epidermal growth factor (EGF)/EGF receptor (EGFR) signalling sustains ECM1 expression through phosphorylating signal transducer and activator of transcription 1 (STAT1) at serine727 (S727), thus enhancing its binding to the <em>ECM1</em> promoter and boosting gene transcription. This process is disrupted during liver inflammation by interferon gamma (IFNγ), which downregulates EGFR and inhibits EGF/EGFR/STAT1-mediated <em>ECM1</em> promoter binding. Mechanistically, IFNγ-induced STAT1 phosphorylation at tyrosine701 (Y701) impairs the binding of p-STAT1 S727 to the <em>ECM1</em> promoter. Additionally, IFNγ induces nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, which repressively binds to the promoter of <em>ECM1</em>, further reducing its expression. These findings are confirmed in several CLD mouse models (n = 2–6). Moreover, AAV8-ECM1 attenuates liver fibrosis and injury in Western diet-fed mice (n = 8–10), counteracting the effects of EGF signalling inhibition and IFNγ/NRF2 activation. In CLD patients (n = 22), ECM1 levels correlate positively with EGFR expression (<em>p</em> &lt;0.0001) and negatively with IFNγ/NRF2 activation (<em>p</em> &lt;0.0001).</div></div><div><h3>Conclusions</h3><div>EGF/STAT1 signalling promotes whereas IFNγ/NRF2 inhibits ECM1 expression in hepatocytes in health or disease, respectively. ECM1 has the potential to be developed as an antifibrotic agent, particularly in inflammation- or reactive oxygen species-driven CLD.</div></div><div><h3>Impact and implications</h3><div>This study reveals the regulatory mechanism of ECM1 in hepatocytes, demonstrating that EGF/STAT1 maintains ECM1 expression to prevent fibrosis, whereas IFNγ/NRF2 signalling inhibits ECM1 during chronic liver inflammation, thereby accelerating disease progression. These findings are important for researchers and clinicians to understand the pathogenesis of liver fibrosis, especially in CLD driven by inflammation or oxidative stress. Clinically, ECM1 levels correlate positively with EGFR expression and negatively with IFNγ/NRF2 activation, providing potential antifibrotic targets for CLD patients.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101423"},"PeriodicalIF":9.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571554","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":"Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease","authors":"Robert F. Schwabe ,&nbsp;Frank Tacke ,&nbsp;Atsushi Sugimoto ,&nbsp;Scott L. Friedman","doi":"10.1016/j.jhepr.2025.101421","DOIUrl":"10.1016/j.jhepr.2025.101421","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than a quarter of the adult population worldwide. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is associated with increased risk of progression to liver fibrosis, cirrhosis and hepatocellular carcinoma, as well as cardiovascular complications. The pathogenesis of MASLD is complex and initiated by altered metabolic signalling circuits between the adipose tissue, muscle, gut and liver. Liver fibrosis is largely driven by the crosstalk of steatotic hepatocytes with macrophages and hepatic stellate cells and constitutes the primary determinant of outcomes in MASLD. Therefore, fibrosis regression is a key therapeutic goal for MASH therapies. Here, we review therapeutic strategies that directly or indirectly reduce liver fibrosis and discuss novel therapeutic concepts. Among these, the targeting of hepatocytes and metabolism have yielded fibrosis reduction in clinical trials and led to the first FDA-approved therapy for MASH. However, these therapies reduce fibrosis only in a subset of patients and have not yet shown benefits beyond the F2-F3 fibrosis stage. Direct antifibrotics and macrophage-based therapies may be more suitable for advanced stages of MASH, but are still in the developmental stage. The arsenal of therapies for MASLD is rapidly expanding and includes macrophage transplantation, hepatocyte-specific oligonucleotides, as well as CAR T cell-based therapies. Integrating these novel therapeutic concepts into stage-specific and/or combination therapies targeting divergent pathogenic mechanisms and cell types is the focus of ongoing research, which may lead to fibrosis reduction in a higher percentage of patients with MASH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101421"},"PeriodicalIF":9.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597384","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":"DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids","authors":"Gen Yamamoto ,&nbsp;Raquel Carvalho-Gontijo Weber ,&nbsp;Wonseok Lee ,&nbsp;Vivian Zhang ,&nbsp;Haeum Jang ,&nbsp;Sadatsugu Sakane ,&nbsp;Xiao Liu ,&nbsp;Hyun Young Kim ,&nbsp;David A. Brenner ,&nbsp;Na Li ,&nbsp;Tatiana Kisseleva","doi":"10.1016/j.jhepr.2025.101415","DOIUrl":"10.1016/j.jhepr.2025.101415","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic dysfunction and alcohol-associated liver disease (MetALD) results in the development of liver steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). &lt;em&gt;De novo&lt;/em&gt; lipogenesis and cholesterol synthesis play an important role in the pathogenesis of MetALD. DHCR7 (7-dehydrocholesterol reductase) regulates the last stages of cholesterol production.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We investigated whether targeting DHCR7 can ameliorate the development of MetALD and HCC using experimental models and 3D human liver spheroids.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Here, we demonstrate that partial genetic ablation of the &lt;em&gt;Dhcr7&lt;/em&gt; gene and pharmacological blockade of DHCR7 activity with the AY9944 inhibitor suppresses hepatic steatosis (↓ lipid area, n = 15; &lt;em&gt;p&lt;/em&gt; &lt;0.001), inflammation (↓ F4/80, n = 6; &lt;em&gt;p&lt;/em&gt; &lt;0.01), fibrosis (↓ Sirius red, n = 6; &lt;em&gt;p&lt;/em&gt; &lt;0.01), and HCC (↓ AFP/YAP, n = 6; &lt;em&gt;p&lt;/em&gt; &lt;0.01) in diethylnitrosamine (DEN)-challenged high-fat diet (HFD) + ethanol (EtOH)-fed mice treated with AY9944 compared with control mice. To translate our findings, the effect of DHCR7 was tested using 3D human liver spheroids, which mimicked MetALD and MetALD-HCC. MetALD liver spheroids were composed of primary human hepatocytes, non-parenchymal cells, and hepatic stellate cells. In contrast, in MetALD-HCC spheroids, the HCC cell line HepG2 was used instead of hepatocytes. Therapeutic administration of AY9944 inhibited inflammation (↓ &lt;em&gt;TNF&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05) and fibrosis in MetALD spheroids (↓ &lt;em&gt;ACTA2&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;COL1A1&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05; &lt;em&gt;TIMP1&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.01; &lt;em&gt;SERPINE1&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05). In turn, dsiRNA-based knockdown of DHCR7 reduced HepG2 proliferation (↓ &lt;em&gt;PCNA&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05; &lt;em&gt;CCNE&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05) and expression of MetALD-HCC markers (↓ &lt;em&gt;AFP&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05; &lt;em&gt;GPC3&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.05; &lt;em&gt;YAP&lt;/em&gt;, &lt;em&gt;p&lt;/em&gt; &lt;0.01).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our data demonstrate that targeting DHCR7 can become a strategy for the treatment of MetALD and HCC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;This study demonstrates the critical role of &lt;em&gt;de novo&lt;/em&gt; lipogenesis and cholesterol synthesis in the pathogenesis of metabolic dysfunction and alcohol-associated liver disease (MetALD) and its progression to hepatocellular carcinoma (HCC). Our findings identified that the upregulation of DHCR7 contributes to the pathogenesis of MetALD and its inhibition suppresses hepatic steatosis, inflammation, fibrosis, and tumor proliferation. These findings are significant for researchers and clinicians, as they establish that genetic and pharmacological inhibition of DHCR7 is effective in both experimental models and translational 3D human liver spheroids. The results uncover the translational potential of DHCR7-targeted therapies fo","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 7","pages":"Article 101415"},"PeriodicalIF":9.5,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221015","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":"Identification of pediatric MASLD using insulin resistance indices","authors":"Kyungchul Song ,&nbsp;Eunju Lee ,&nbsp;Hye Sun Lee ,&nbsp;Young Hoon Youn ,&nbsp;Su Jung Baik ,&nbsp;Hyun Joo Shin ,&nbsp;Hyun Wook Chae ,&nbsp;Ji-Won Lee ,&nbsp;Yu-Jin Kwon","doi":"10.1016/j.jhepr.2025.101419","DOIUrl":"10.1016/j.jhepr.2025.101419","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;We investigated the triglyceride-to-high density lipoprotein (HDL) ratio (TG/HDL), triglyceride–glucose index (TyG), single-point insulin sensitivity estimator (SPISE), and metabolic score for insulin resistance (METS-IR) as potential predictors of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) by addressing the limited research on insulin-resistance markers in this population.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This cross-sectional study included data from 1,150 and 260 youths from the National Health and Nutrition Examination Survey (NHANES) and a real-world clinic, respectively. Hepatic steatosis was assessed using transient elastography and abdominal sonography. Logistic regression analysis was performed using MASLD as the dependent variable. Receiver operating characteristic (ROC) curves were used to evaluate predictability.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The MASLD group had higher TG/HDL, TyG, METS-IR, and obesity proportions but lower SPISE than the normal group in both NHANES and real-world data. All markers were significantly related to MASLD in logistic regression analyses, even after adjusting for age and sex, in both the NHANES and real-world clinic data (all &lt;em&gt;p&lt;/em&gt; &lt;0.001). The areas under the ROC curves (AUCs) for SPISE and METS-IR were 0.91 and 0.91 in the total group, 0.92 and 0.92 in the male group, and 0.90 and 0.89 in the female group, respectively—all higher than those for TG/HDL and TyG in the NHANES dataset (all &lt;em&gt;p&lt;/em&gt; &lt;0.001). In the real-world clinical data, the AUCs of SPISE and METS-IR were significantly higher than those of TG/HDL and TyG in the total and male groups (all &lt;em&gt;p&lt;/em&gt; &lt;0.001). In the female group, the AUC for SPISE was significantly higher than that for TG/HDL or TyG.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;METS-IR and SPISE are effective, non-invasive markers for predicting pediatric MASLD, which offer valuable tools for early detection and improved clinical management.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;The increasing prevalence of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and its strong association with cardiometabolic risk factors underscore the need for effective early detection tools. Our study demonstrates that single-point insulin sensitivity estimator (SPISE) and metabolic score for insulin resistance (METS-IR) are superior, non-invasive markers for predicting MASLD in children and adolescents, with validated cut-off values applicable to both population-based and real-world clinical settings. These findings are particularly relevant for clinicians and healthcare policymakers, as they provide practical, easily accessible screening tools derived from routine laboratory tests, aiding in the early identification and risk stratification of pediatric MASLD. However, given the study’s retrospective design and variations in diagnostic methods across datasets, fu","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 7","pages":"Article 101419"},"PeriodicalIF":9.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205555","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 EIF4A1 is effective against human intrahepatic cholangiocarcinoma","authors":"Wunan Mi ,&nbsp;Antonio Cigliano ,&nbsp;Grazia Galleri ,&nbsp;Isabella Gigante ,&nbsp;Sara Martina Steinmann ,&nbsp;Ezgi Cibali ,&nbsp;Marina Serra ,&nbsp;Giovanni Mario Pes ,&nbsp;Denise Schloesser ,&nbsp;Elena Pizzuto ,&nbsp;Heiko Siegmund ,&nbsp;Claudia Fischer ,&nbsp;Anna Saborowski ,&nbsp;Gianluigi Giannelli ,&nbsp;Matthias Evert ,&nbsp;Luc Johannes Wilhelmus van der Laan ,&nbsp;Monique Maria Andrea Verstegen ,&nbsp;Diego Francesco Calvisi","doi":"10.1016/j.jhepr.2025.101416","DOIUrl":"10.1016/j.jhepr.2025.101416","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary liver tumor, characterized by clinical aggressiveness, dismal outcome, and limited therapeutic options. Thus, innovative treatments are urgently required to improve the prognosis of patients with iCCA.</div></div><div><h3>Methods</h3><div>In this study, we determined the pathogenetic and therapeutic role of eukaryotic initiation factor 4A1 (EIF4A1), a subunit of the eIF4F complex involved in translation initiation, in human iCCA.</div></div><div><h3>Results</h3><div>Preinvasive (n = 12), invasive (n = 162), and metastatic (n = 14) iCCA lesions exhibited ubiquitous eIF4A1 upregulation. In addition, <em>eIF4A1</em> mRNA levels from 42 specimens showed a significantly higher expression in iCCA samples compared with non-tumorous tissues (<em>p</em> &lt;0.0001) or large duct-type lesions (<em>p</em> = 0.020). Furthermore, <em>eIF4A1</em> expression was inversely associated with patient prognosis (<em>p</em> &lt;0.001). Moreover, zotatifin, an eIF4A1-specific inhibitor in clinical trials, significantly reduced the growth of iCCA cell lines, iCCA cancer-associated fibroblasts (CAFs), and patient-derived tumor organoids. At the metabolic level, zotatifin decreased glycolysis of iCCA cells without affecting mitochondrial respiration. Moreover, the Bcl-xl inhibitors A-1155463 and DT2216 profoundly augmented apoptotic cell death when administered in association with zotatifin.</div></div><div><h3>Conclusions</h3><div>The data highlight eIF4A1 as a potential target for treating iCCA. Combined inhibition of eIF4A1 and Bcl-xl could offer an effective therapeutic strategy against this deadly disease.</div></div><div><h3>Impact and implications</h3><div>Dysregulation of the translational machinery is a hallmark of cancer, often linked to tumor progression and poor prognosis. This study underscores the potential of zotatifin, a specific inhibitor of EIF4A1 (an essential component of translation initiation) to inhibit the growth of iCCA cells. In addition, zotatifin demonstrated a synergistic effect when used in combination with the Bcl-xl inhibitors A-1155463 and DT2216, significantly enhancing cell apoptosis. Although this investigation did not include an <em>in vivo</em> model, its results, derived from iCCA cell lines, patient-derived organoids, and CAFs, are consistent with the encouraging preliminary results of zotatifin in clinical trials. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 7","pages":"Article 101416"},"PeriodicalIF":9.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221016","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":"Inflammation in MASLD progression and cancer","authors":"Yeonsoo Kim ,&nbsp;Yunseo Park ,&nbsp;Hyunsoo Rho ,&nbsp;Tiantian Yao ,&nbsp;Bin Gao ,&nbsp;Seonghwan Hwang","doi":"10.1016/j.jhepr.2025.101414","DOIUrl":"10.1016/j.jhepr.2025.101414","url":null,"abstract":"<div><div>Steatotic liver diseases include metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease, and metabolic dysfunction and alcohol-related liver disease (MetALD), encompassing a spectrum of metabolic liver disorders that range from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Steatotic liver disease is primarily driven by alcohol consumption and metabolic dysfunction, making it the leading cause of chronic liver disease. Steatosis is defined by excessive fat accumulation in the liver without significant liver injury or inflammation. In contrast, inflammation is the predominant factor that drives the progression of steatosis to steatohepatitis and, ultimately, to cancer. In this review, we summarise the current understanding of the inflammatory mechanisms underlying the pathogenesis of MASLD and explore molecular targets that may offer the potential for pharmacological intervention. Additionally, given the pathological similarities between MASLD and MetALD, relevant inflammatory pathways in MetALD are briefly discussed to underscore both commonalities and key distinctions between the two conditions.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101414"},"PeriodicalIF":9.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501326","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}