JHEP Reports最新文献

{"title":"Hepatic flares, their immune signatures, and ALT variability after nucleos(t)ide analogue cessation in HBeAg-negative hepatitis B.","authors":"Marte Holmberg, Annika Niehrs, Olav Dalgard, Nega Berhe, Hailemichael Desalegn, Soo Aleman, Nina Weis, Tore Stenstad, Lars Heggelund, Ellen Samuelsen, Lars Normann Karlsen, Karin Lindahl, Elisabeth Kleppa, Anni Assing Winckelmann, Pascal Brugger-Synnes, Hans Erling Simonsen, Jan Svendsen, Niklas K Björkström, Dag Henrik Reikvam, Asgeir Johannessen","doi":"10.1016/j.jhepr.2026.101875","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101875","url":null,"abstract":"<p><strong>Background and aims: </strong>Hepatic flares frequently occur after nucleos(t)ide analogue (NA) cessation in patients with chronic hepatitis B (CHB) and can be beneficial (\"good flares\") or harmful (\"bad flares\"). We characterised flares after NA cessation aiming to identify predictors and immunological correlates of good and bad flares.</p><p><strong>Methods: </strong>This study was nested in the prospective Nuc-Stop study, in which 127 patients with e-antigen negative CHB discontinued NA treatment with a 36-month follow-up. Flares were defined as an ALT increase >2× the upper limit of normal or >2× baseline. Predictors of flares were identified by logistic regression. In 32 patients with flares without treatment restart, we compared clinical characteristics and soluble immune marker profiles of good flares (hepatitis B surface antigen (HBsAg) loss or >1 log₁₀ decline or sustained virological control) and bad flares (neither HBsAg decline nor virological control).</p><p><strong>Results: </strong>Flares occurred in 58.3% of patients. Age (per 1-year increment; adjusted odds ratio (aOR), 1.07; 95% confidence interval (CI) 1.02-1.12) and end-of-treatment HBsAg level (per 1 log₁₀ IU/mL increment; aOR, 2.09; 95% CI 1.20-3.62) independently predicted flares. Good flares displayed less ALT variability after the initial spike than bad flares (standard deviation 9.7 vs. 22.7 U/L, p=0.002). Analysis of soluble immune markers confirmed distinct clusters for good and bad flares at end-of-treatment, with higher serum levels of specific proteins in good flares (e.g. IL-13, TRAIL) and bad flares (e.g. CXCL11, OPG, TNF).</p><p><strong>Conclusions: </strong>Flares occurred in over half the patients after NA cessation and were associated with age and end-of-treatment HBsAg levels. ALT variability following the initial flare and soluble marker profiles might serve as prognostic factors and distinguish good from bad flares.</p><p><strong>Impact and implications: </strong>Nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B may facilitate functional cure, but hepatic flares are common and potentially detrimental, making careful patient selection essential. In this prospective, multicentre trial, flares occurred in over half of the patients, with severe flares in 12.6%. Increasing age and higher end-of-treatment HBsAg levels were predictors of flares and should be considered when deciding on treatment discontinuation. Close monitoring, particularly during the first six months, is critical for safe patient management, while ALT variability following the initial flare and soluble immune markers may help differentiate good from bad flares and guide retreatment decisions.</p><p><strong>Clinical trial number (for the nuc-stop study): </strong>ClinicalTrials.gov, Identifier: NCT03681132.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101875"},"PeriodicalIF":7.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815392","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":"Accurate detection of cholangiocarcinoma in primary sclerosing cholangitis by DNA methylation biomarkers in bile and plasma.","authors":"Hege Marie Vedeld, Sigurd Breder, Heidi Pharo, Hans Petter Brodal, Evy Marie Adolfsen, Sara Brandt-Winge, Erik von Seth, Marit Mæhle Grimsrud, Sheraz Yaqub, Tom H Karlsen, Krzyztof Grzyb, Vemund Paulsen, Martti A Färkkilä, Annika Bergquist, Lars Aabakken, Kirsten M Boberg, Trine Folseraas, Guro E Lind","doi":"10.1016/j.jhepr.2026.101876","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101876","url":null,"abstract":"<p><strong>Background & aims: </strong>Current methods for cholangiocarcinoma (CCA) detection in primary sclerosing cholangitis (PSC) lack accuracy, often leading to late, non-curative diagnoses. This study aimed to identify DNA methylation biomarkers in liquid biopsies for earlier and more accurate CCA detection.</p><p><strong>Methods: </strong>Reduced representation bisulfite sequencing (RRBS) was used to analyze tissue samples from individuals with CCA (n=10) and PSC (n=9), yielding 12 candidate DNA methylation biomarkers. Following droplet digital PCR (ddPCR) assay development, quality control, and verification in tissue, four biomarkers were selected for evaluation in bile (n = 272) and plasma (n = 128) samples from individuals with PSC and/or CCA collected across three different hospitals.</p><p><strong>Results: </strong>Four biomarkers demonstrated perfect discrimination (AUC=1.00) between PSC-associated CCA (PSC-CCA) and PSC alone in tissue samples. In bile, all four biomarkers achieved an AUC >0.9 for distinguishing PSC-CCA (n=20) from PSC alone (n=207). A two-biomarker panel (5-42952178 and PRKCB) achieved 95% sensitivity and 90% specificity, while adding KCNA6 and ZFP82 increased specificity to 97% with sensitivity maintained at 90%. Notably, the two-biomarker bile panel successfully detected all eight CCA cases (100% sensitivity) in samples collected 3-12 months prior to diagnosis by conventional methods. Performance was lower in plasma, where an alternative two-biomarker panel (KCNA6 and PRKCB) achieved 70% sensitivity and 90% specificity for distinguishing PSC-CCA (n=17) and PSC alone (n=101).</p><p><strong>Conclusions: </strong>Four DNA methylation biomarkers accurately discriminate CCA from PSC in bile, with lower performance in plasma. Their ability to detect CCA months before clinical diagnosis supports further evaluation in prospective studies to enable earlier, potentially curative intervention in PSC.</p><p><strong>Impact and implications: </strong>This study demonstrates that liquid biopsy-based DNA methylation biomarkers offer high sensitivity and specificity for early detection of CCA in individuals with PSC, directly addressing a critical unmet need. Early and accurate detection may enable timely surgical intervention, with the potential to significantly improve survival in this high-risk group. Both bile and plasma samples are accessible via routine clinical care, and implementation of such biomarkers would not introduce additional procedural risk. If validated in prospective studies, these biomarkers could transform standard CCA surveillance in PSC by providing a minimally invasive, reliable tool for longitudinal monitoring and earlier detection and intervention.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101876"},"PeriodicalIF":7.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815332","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":"Comparison of patients with HBV-related HCC with and without MASLD after liver transplantation.","authors":"Huigang Li, Jinyan Chen, Chenghao Cao, Shusen Zheng, Xiao Xu, Di Lu","doi":"10.1016/j.jhepr.2026.101877","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101877","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101877"},"PeriodicalIF":7.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815353","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":"Clinical features and management for CDK4/6 inhibitor-DILI.","authors":"Mar Riveiro-Barciela, Paula Esteban, Kreina Sharela Vega-Cano, Beatriz Mateos, Elena López Miranda, Pablo Jara, Miguel Martín, Sonia Alonso López, Magdalena Salcedo, Xavier Forns, Isabel García-Fructuoso, Olga Martínez-Sáez, José Pinazo-Bandera, Miren García-Cortés, Nuria Ribelles, Álvaro Romanos Nanclares, Daniel Morchón-Araujo, César A Rodríguez, Rebeca Lozano, Raquel Domínguez-Gómez, Mónica Cejuela, Julio Torres-Sempere, Juan Carlos Ruiz-Cobo, Ares Villagrasa, Esther Zamora, Maria Buti, Meritxell Bellet","doi":"10.1016/j.jhepr.2026.101873","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101873","url":null,"abstract":"<p><strong>Background & aims: </strong>Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) -ribociclib, abemaciclib, palbociclib- are the standard-of-care for metastatic breast cancer. Although hepatotoxicity is a frequent adverse event, data on CDK4/6i drug-induced liver injury (DILI) remains scarce. We aimed to define the incidence, clinical presentation, severity, management and relapse of CDK4/6i-related DILI in a large real-world cohort.</p><p><strong>Methods: </strong>Retrospective multicentre study including all patients who developed ≥ grade-2 DILI (ALT/AST >3x ULN) while receiving CDK4/6i between January/2018 and December/2022. Severity was assessed according to CTCAEv5 and DILI-IEWG criteria.</p><p><strong>Results: </strong>Among 2,222 CDK4/6i-treated patients, 100 (4.5%, 95% CI 3.7%-5.4%) developed DILI. Incidence was significantly higher for ribociclib (8.3%, 95% CI 6.3%-10.7%) and abemaciclib (6.7%, 95% CI 4.6%-9.3%) than for palbociclib (1.4%, 95% CI 0.8%-2.2%) (Difference, p<0.001). Most cases were grade 2 or 3 (CTCAE) and mild (DILI-IEWG), although moderate DILI (bilirubin >2x ULN, n=12) occurred with all three CDK4/6i. The most frequent pattern was hepatocellular, while cholestatic was mainly observed with abemaciclib. Liver biopsy findings (n=11) were heterogeneous and, together with biochemical results, did not support an immune-mediated mechanism as the primary driver. Corticosteroids (n=20) did not impact time to grade-1 or ALT normalization. DILI recurred in 28.2% of CDK4/6i rechallenges (n=85). Among ribociclib-treated patients, rechallenge with an alternative CDK4/6i was associated with lower risk of recurrence (p=0.010).</p><p><strong>Conclusions: </strong>DILI due to ribociclib and abemaciclib are more common that with palbociclib. The absence of immune-mediated features and the limited benefit of corticosteroids question their routine use. After CDK4/6i reintroduction, DILI recurrence rate was 28%. Standardized management is needed, particularly following the approval of ribociclib and abemaciclib as adjuvant therapy.</p><p><strong>Impact and implications: </strong>● Although hepatotoxicity is a frequent adverse event, real-world data on CDK4/6i drug-induced liver injury (DILI) remains scarce.● DILI associated with ribociclib and abemaciclib is more common than for palbociclib, though moderate DILI (bilirubin >2x normality) was observed with the three drugs.● The absence of immune-mediated features and the limited benefit of corticosteroids question their routine use in CDK4/6i drug-induced liver injury.● Relapse of DILI after rechallenge with a CDK4/6i was 28%, with all cases presenting as mild.● The increasing use of CDK4/6i (metastatic breast cancer and ribociclib and abemaciclib as adjuvant therapy) highlights the need of standardizing the management of CDK4/6i drug-induced liver injury.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101873"},"PeriodicalIF":7.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815360","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":"Vessels Encapsulating Tumor Clusters predict better outcomes in advanced hepatocellular carcinoma treated with atezolizumab-bevacizumab.","authors":"Alexandre Sayadi, Claudia Campani, Astrid Laurent-Bellue, Marianne Ziol, Luca Di Tommaso, Etienne Becht, Benoit Terris, Julien Calderaro, Luca Messerini, Miguel Albuquerque, Federico Lipsich, Carolina Gutierrez, Marion Dhooge, Lisa Lellouche, Giuliana Amaddeo, Alina Pascale, Olivier Rosmorduc, Fabio Marra, Lorenza Rimassa, Marco Dioguardi Burgio, Jean-Charles Nault, Mohamed Bouattour, Valérie Paradis, Aurélie Beaufrère","doi":"10.1016/j.jhepr.2026.101874","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101874","url":null,"abstract":"<p><strong>Background & aims: </strong>Atezolizumab+bevacizumab and durvalumab+tremelimumab are the standard first-line therapies for advanced HCC. Histological variables routinely associated with outcomes remain poorly described. We aimed to assess the prognostic and predictive value of VETC in this setting.</p><p><strong>Methods: </strong>We retrospectively analyzed 208 patients in a discovery cohort with advanced HCC treated with atezolizumab+bevacizumab and available pre-treatment biopsies, and 163 patients in a validation cohort, including 99 treated with atezolizumab+bevacizumab and 64 with durvalumab+tremelimumab. In addition to baseline clinico-biological variables, we assessed histological features, including Vessels Encapsulating Tumor Clusters (VETC) phenotype, defined as complete (≥55% of tumor area), or incomplete (1-54% of tumor area). Prognostic impacts were evaluated using multivariable Cox models.</p><p><strong>Results: </strong>In the discovery cohort, the complete VETC phenotype (n=32) displayed the highest objective response rate in the cohort (66% vs 37% in non- or incomplete-VETC-HCC, p=0.002), according to mRECIST. The complete VETC phenotype was independently associated with better progression-free survival (PFS) (Hazard Ratio [HR] 0.42, 95%CI 0.26 - 0.69, p < 0.001) and overall survival (OS) (HR 0.46, 95%CI 0.26 - 0.82, p=0.008). In the validation cohort, complete VETC-HCC was associated with worse outcomes in patients treated with durvalumab+tremelimumab (PFS: HR 2.44, 95%CI 1.12, 5.29, p=0.024; OS: HR 3.90, 95%CI 1.66, 9.15, p=0.002). Patients with complete VETC HCC and treated with atezolizumab+bevacizumab had longer survival than patients with complete VETC HCC and treated with durvalumab+tremelimumab (PFS: HR 0.43, 95%CI 0.17, 1.06, p=0.07; OS: HR 0.19, 95%CI 0.07, 0.51, p=0.001).</p><p><strong>Conclusion: </strong>We identified complete VETC as a potential predictive marker of outcomes in patients with advanced HCC and treated with atezolizumab+bevacizumab or durvalumab+tremelimumab. Prospective validation of these findings is warranted.</p><p><strong>Impact and implications: </strong>Routinely assessable histological variables associated with response and survival are still lacking in patients with advanced HCC treated with atezolizumab+bevacizumab. In this study, we identified and validated, in a multicentric series of 371 pre-therapeutic biopsies, the complete VETC phenotype as a predictive factor for progression-free survival and overall survival in patients with HCC treated with atezolizumab+bevacizumab compared to those treated with durvalumab+tremelimumab. The VETC phenotype is easily assessable in routine practice on biopsy and could help select first-line therapy, although prospective validation of these results remains necessary.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101874"},"PeriodicalIF":7.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815314","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":"FASN-dependent lipogenesis controls macrophage efferocytosis in alcohol-associated liver disease.","authors":"Chen Chen, Xiaoyong Jiang, Hao Li, Panpan Huang, Honghai Xu, Hua Wang, Chaojie Hu","doi":"10.1016/j.jhepr.2026.101872","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101872","url":null,"abstract":"<p><strong>Background & aims: </strong>Defective clearance of apoptotic hepatocytes contributes to inflammation and progression of alcohol-associated liver disease (ALD), but the mechanisms regulating macrophage efferocytosis during alcohol exposure remain unclear. We investigated whether fatty acid synthase (FASN)-dependent lipid metabolism controls hepatic macrophage efferocytosis in ALD.</p><p><strong>Methods: </strong>Human liver tissues from patients with alcohol-related cirrhosis (AC) and controls (n = 18/group), together with experimental ALD mouse models (n = 6/group), were analyzed for hepatocyte apoptosis and hepatic macrophage alterations. Transcriptomic profiling (n = 3/group), pharmacological inhibition, and myeloid- or Kupffer cell-specific Fasn knockout mice (n = 6/group) were used to define the role and mechanism of FASN-mediated lipogenesis in macrophage efferocytosis.</p><p><strong>Results: </strong>In patients with AC, hepatocyte apoptosis was markedly increased compared with controls (p < 0.0001), accompanied by increased accumulation of CD68-positive inflammatory macrophages (p < 0.001). In experimental ALD mice, hepatocyte apoptosis and monocyte-derived macrophage infiltration were also significantly increased (p < 0.0001). Mechanistically, ethanol impaired macrophage efferocytosis by more than 80% (p < 0.01). This was associated with inhibition of the PI3K/AKT/SREBP1 pathway, reduced FASN expression, and suppressed de novo lipogenesis. Reduced FASN expression decreased NRF2 activity and impaired TREM2 transcription, resulting in defective clearance of apoptotic cells. TREM2-positive hepatic macrophages were markedly reduced in both human AC and murine ALD (p < 0.0001). Consistently, Kupffer cell-specific Fasn deletion significantly aggravated hepatocyte apoptosis and liver injury in vivo (p < 0.01).</p><p><strong>Conclusions: </strong>Alcohol impairs macrophage efferocytosis by suppressing the PI3K/AKT/SREBP1-FASN-NRF2-TREM2 axis. Disruption of this lipogenic program promotes hepatocyte apoptosis and liver inflammation in ALD.</p><p><strong>Impact and implications: </strong>Alcohol-associated liver disease is characterized by hepatocyte death and ongoing inflammation, but the mechanisms that connect these processes to macrophage efferocytosis remain poorly understood. Our research revealed that ethanol suppresses FASN-dependent de novo lipogenesis and downstream NRF2-TREM2 signaling in hepatic macrophages. Impairment of lipogenesis compromises efferocytosis, leading to an accumulation of apoptotic hepatocytes and increased monocyte infiltration. These findings underscore the potential of targeting macrophage lipid metabolism as a therapeutic strategy in ALD. However, further translational validation is needed before clinical application.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101872"},"PeriodicalIF":7.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815341","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":"ANXA1-FPR1 signaling in myeloid cells drives MASH by elevating S100A4/A11.","authors":"Siting Yang, Shengying Qian, Liu Yang, Yanghuan He, Shujun Ge, Xinhuan Fu, Siyue Dong, Ru Ya, Yingfen Chen, Ningning Ma, Peng Xiao, Ziling Zhang, Yue Zhou, Yuanwen Chen, Yan Wang, Yong He","doi":"10.1016/j.jhepr.2026.101869","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101869","url":null,"abstract":"<p><strong>Background & aims: </strong>Inflammation plays a central role in the development of metabolic dysfunction-associated steatohepatitis (MASH). Formyl peptide receptor 1 (FPR1) in myeloid cells emerges as a crucial factor associated with the inflammatory response; however, whether and how FPR1 signaling affects MASH development remain largely unknown.</p><p><strong>Methods: </strong>Neutrophil-specific Fpr1 knockout mice and macrophage-specific Fpr1 knockout mice were generated, and subjected to high-fat high-cholesterol (HFHC, N=6-10) or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD, N=5-9) feeding.</p><p><strong>Results: </strong>After MASH diet feeding, both neutrophil and macrophage-specific Fpr1 knockout mice had lower inflammatory cell infiltration and less degree of liver fibrosis than control mice (p<0.05-0.001). Administration of a selective inhibitor of FPR1, Cyclosporin H, robustly ameliorated mouse MASH in vivo and the 3D NAC-organ human MASH model in vitro (reduction in fibrosis area by 50%,p<0.001). Mechanistically, transcriptomic analysis revealed that Fpr1 deficiency in myeloid cells limited inflammatory cell chemotaxis and migration, which were closely related with the downregulation of S100a4 and S100a11. Moreover, neutrophil-derived annexin A1 (ANXA1) activated FPR1 signaling in neutrophils and macrophages during MASH, resulting in upregulation of proinflammatory S100A4 and S100A11 (p<0.05-0.01). Importantly, hepatic and serum levels of ANXA1, S100A4, and S100A11 were significantly elevated in patients with MASH (N=15 for serum samples or 20 for liver samples), which positively correlated with the hepatic levels of several proinflammatory genes and fibrogenic genes (p<0.05).</p><p><strong>Conclusions: </strong>The ANXA1-FPR1 axis in myeloid cells worsens MASH by elevating S100A4 and S100A11 levels, suggesting that pharmacological inhibition of FPR1 signaling is a promising strategy to ameliorate MASH.</p><p><strong>Impact and implications: </strong>FPR1 in myeloid cells is a crucial factor associated with the inflammatory response; however, whether FPR1 signaling affects MASH development remains largely unknown. In this study, we demonstrated that Fpr1 deficiency in myeloid cells and administration of an FPR1 inhibitor robustly limit MASH-related fibrosis, which is closely related with the downregulation of proinflammatory S100A4 and S100A11. In addition, neutrophil-derived ANXA1 elevates the expression of S100A4 and S100A11 in neutrophils and macrophages by activating FPR1 signaling, suggesting that the ANXA1-FPR1-S100A4/A11 axis plays an important role in worsening MASH.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101869"},"PeriodicalIF":7.5,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771893","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":"Robust HLA-B-restricted CD8+ T cell responses in chronic HBV infection.","authors":"Julia Lang-Meli, Anna-Lena Denecke, Johannes Ptok, Philipp Ehrenmann, Elahe Salimi Alizei, Hendrik Luxenburger, Michelle Maas, Muthamia Kiraithe, Felix Jacobi, Giuseppe Rusignuolo, Isabel Schulien, Emma Gostick, Sian Llewellyn-Lacey, Florian Emmerich, Bertram Bengsch, Tobias Boettler, David A Price, Andreas Walker, Jörg Timm, Robert Thimme, Maike Hofmann, Christoph Neumann-Haefelin","doi":"10.1016/j.jhepr.2026.101868","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101868","url":null,"abstract":"<p><strong>Background/aims: </strong>Function and quantity of CD8+ T cell responses is superior in acute versus chronic HBV infection. Whether different HBV-derived epitopes are targeted in these distinct courses of HBV infection remains, however, incompletely understood.</p><p><strong>Methods: </strong>PBMC from 56 patients with chronic HBV infection genotype D and 32 patients with acute or resolved HBV infection were screened for responses to overlapping peptides (18mers) covering the full HBV genotype D proteome with subsequent comprehensive experimental fine-mapping of the minimal optimal epitopes.</p><p><strong>Results: </strong>Patients with acute HBV infection showed a broad HBV-specific CD8+ T cell epitope repertoire. After spontaneous resolution, the strength of HBV-specific CD8 T cell responses decreased, while the broad epitope landscape was preserved. In chronic HBV infection, the specificity of HBV-specific CD8+ T cell responses to HBV antigens was shifted, with a lack of functional HBsAg-specific CD8+ T cell responses (p=0.0007), as recently described. Interestingly, in patients with chronic HBV infection significantly more HLA-B- than HLA-A-restricted HBV-specific CD8+ T cell responses were detectable (33 and 19 responses, respectively), while this distribution was balanced in acute/resolved HBV infection (16 and 27 responses, respectively; p=0.0364). Most (79.6%) of the detected responses showed conserved autologous viral sequences. This observation was confirmed in a broader sequence dataset with no evidence for HLA-B driven CD8+ T cell selection pressure.</p><p><strong>Conclusions: </strong>In contrast to acute/resolved infection, conserved HLA-B-restricted epitopes are dominant in chronic HBV infection, making them interesting candidates for immunotherapeutic approaches towards functional cure of chronic HBV infection.</p><p><strong>Impact and implications: </strong>To date, there is no treatment to achieve functional cure of chronic HBV infection. Immunotherapy boosting dysfunctional HBV-specific CD8+ T cells is an interesting approach, but relies on selection of optimal target epitopes. Using an unbiased approach, we found that the HBV-specific CD8+ T cell epitope repertoire in chronic HBV infection is not well covered by previously described epitopes. We characterized 28 novel, primarily HLA-B-restricted epitopes that are dominantly targeted in chronic HBV infection and might be used as a \"toolbox\" for immunological studies and the development of immunotherapeutic approaches.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101868"},"PeriodicalIF":7.5,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771911","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 future of hepatology: Preventing liver disease together with the public, scientists and artificial intelligence.","authors":"Benjamin P M Laevens, Corinna Meeßen, Frank P Pijpers, Tony Bruns, Yazhou Chen, Rohit Loomba, Niharika Jakhar, Katrin Arning, Kai M Schneider, Carolin V Schneider","doi":"10.1016/j.jhepr.2026.101846","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101846","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and aims: &lt;/strong&gt;The coming decades will bring important challenges for medicine, including hepatology, such as rising healthcare costs and the increasing role of artificial intelligence (AI). Addressing these challenges depends partly on how the scientific community builds public trust and support for long-term policy solutions. The aim of this paper is to explore how broader societal involvement in hepatology through participatory medicine, centred on collaboration between laypeople, clinicians, researchers and intelligent systems, may contribute to research, prevention and public engagement. Such approaches stimulate partnerships that benefit lay contributors and researchers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Examples from other scientific domains, including astronomy (Galaxy Zoo, involving over 200,000 volunteers classifying galaxies), molecular biology (EteRNA, a gamified platform where tens of thousands of players solve RNA folding puzzles), meteorology (WOW, integrating data from citizen weather stations) and traffic monitoring (Telraam, where citizens deploy street-level traffic sensors) show how citizen participation and AI can form co-learning loops. Drawing inspiration from these four case studies, we develop six new participatory hepatology projects.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;These projects fall into two categories based on participants. Four are public-led: Liver Zoo (medical imaging annotation), Liver Cache (geocaching-based prevention and awareness), LiverQuest (gamified prevention and behavioural reflection) and Heporama (community-driven aflatoxin surveillance). Two are patient-centric: Liver Cancer Wisdom Bank (patient knowledge repository) and Liver4Mind (neurocognitive monitoring in cirrhosis and encephalopathy).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;These proposals illustrate how participatory approaches may strengthen trust, public engagement and innovation in hepatology, supporting societal involvement in research and prevention. Intended as catalysts for dialogue, we invite the hepatology community to shape these and related participatory initiatives, thereby strengthening communication and public education while positioning hepatology at the forefront of innovative and trust-building medicine.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;This study sets out the case for expanding participatory medicine in hepatology beyond patient-centred research to also include the general public, addressing persistent gaps in prevention, awareness, and representative data in an era of increasing AI use. By adapting established citizen science models from other disciplines into six hepatology-specific project archetypes, the study shows how public engagement can support earlier risk awareness and prevention while providing complementary behavioural, environmental, and perceptual insights, beyond those available in clinical settings. These findings are particularly relevant for hepatologists, public health res","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101846"},"PeriodicalIF":7.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771902","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 subset of hepatic fibroblasts marked by Gli1 expression generates portal fibrosis and promotes ductular reaction.","authors":"Mariana Amaral Raposo, Haquima El Mourabit, Wenrui Gao, Mirko Minini, Romain Morichon, Laura Fouassier, Dominique Wendum, Mário José Abdalla Saad, Andrey Dos Santos, Jérémie Gautheron, Nicolas Chignard, Chantal Housset, Axelle Cadoret, Sara Lemoinne","doi":"10.1016/j.jhepr.2026.101819","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101819","url":null,"abstract":"<p><strong>Background & aims: </strong>Gli1+ cells were previously described as myofibroblast precursors. We aimed to delineate the identity of Gli1+ cells and their contribution to wound healing in liver.</p><p><strong>Methods: </strong>Gli1+ cells were analyzed in normal mouse liver by scRNAseq (n=3). Genetic cell fate tracing and depletion of Gli1+ cells were achieved in male mice, undergoing cholestatic injury induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or bile duct ligation (BDL), and metabolic-dysfunction associated steatohepatitis (MASH). Gli1 expression was examined by FISH in human liver (n=16). Cell interactions were assessed using organoids.</p><p><strong>Results: </strong>In normal liver, Gli1 demarcated a subpopulation (11.8%) of periductal portal fibroblasts, which transcriptome pertains to extracellular matrix and structure organization. In liver injury, Gli1+ fibroblasts accumulated with fibrosis as multilayers around bile ducts and discontinuously along the inner border of the ductular reaction, predominantly in biliary models and less markedly in MASH. In humans, periductal Gli1+ cells were present in normal liver and accumulated in primary sclerosing cholangitis and, to a lesser extent, in MASH, notably alongside the ductular reaction in late-stage diseases. Coculture of cholangiocyte organoids with Gli1+ fibroblasts showed bi-directional interactions fostering proliferation of both cell types. Genetic depletion of Gli1+ cells (n ≥ 4/group) caused a marked reduction of fibrosis, assessed by Sirius red area, in DDC-fed and BDL mice after one week (p<0.01) and of ductular reaction, assessed by cytokeratin-19+ cell count in DDC (p<0.01), although cholestatic injury persisted or even increased.</p><p><strong>Conclusions: </strong>Gli1 demarcates a subpopulation of fibroblasts that play a key role in the wound healing process combining portal fibrosis and ductular reaction notably in biliary diseases.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101819"},"PeriodicalIF":7.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771875","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}