Hepatology Communications最新文献

{"title":"Electronic decision aids enhance management of primary care patients with steatotic liver disease: Proof of concept pilot study.","authors":"Ashley Spann, Kristy Bishop, Sarah Marbach, Xiangyu Ji, James Slaughter, Asli Weitkamp, Shane Stenner, Scott Nelson, Christine Lopez, Cecelia Theobald, Manhal Izzy","doi":"10.1097/HC9.0000000000000794","DOIUrl":"10.1097/HC9.0000000000000794","url":null,"abstract":"<p><strong>Background: </strong>The approach to appropriate risk stratification for metabolic dysfunction-associated steatotic liver disease (MASLD) is variable, and the adoption of non-invasive liver disease assessments in clinical practice is suboptimal. In this study, we implemented an electronic decision support tool for primary care patients with MASLD to assess its influence on linkage to care.</p><p><strong>Methods: </strong>We performed a prospective, before-and-after pilot study in which post-implementation providers were presented with an electronic decision aid automating non-invasive liver disease assessments with the Fibrosis-4 score and providing individualized, guideline-directed recommendations. Patients were included if attending an outpatient primary care visit with a study provider, had a pre-existing diagnostic code for MASLD, and had not established care with a hepatologist in the 3 years before the office visit. The primary outcome was linkage to care, defined as adherence to guideline-directed recommendations for the next step of care. A total of 503 encounters were included, accounting for 301 unique patients.</p><p><strong>Results: </strong>Provider adherence to guideline-directed clinical recommendations increased from 29.7% to 45.8% post-implementation (p<0.001). The effect of this intervention remained significant when controlling for patient age, race, sex, resident physician involvement in the clinic visit, and concomitant comorbidities of diabetes, hypertension, and hyperlipidemia (OR 2.11 [95% CI 1.42-3.14]; p<0.001). There was a modest increase in the number of referrals to hepatology post-implementation (2.3%-7.1%; OR 3.27 [95% CI 1.33-9.18]; p=0.014).</p><p><strong>Conclusions: </strong>In conclusion, we present a novel, electronically integrated, innovative methodology for direct delivery of individualized guidance for the management of patients with MASLD that significantly enhanced the direction of care toward necessary guideline-directed liver assessments.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological study of the tumor microenvironment after neoadjuvant therapy in hepatocellular carcinoma: Difference of TACE combined with antiangiogenics and immunotherapy.","authors":"Xintao He, Yanhong Liu, Tianyi Dai, Aihua Yang, Jianan Shen, Zexuan Hui, Jie Shen, Jun Chen","doi":"10.1097/HC9.0000000000000787","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000787","url":null,"abstract":"<p><strong>Background: </strong>HCC is the leading form of primary liver cancer worldwide. Transcatheter arterial chemoembolization (T) is commonly used to treat unresectable tumors. T combined with antiangiogenic therapy and immunotherapy (AI) has shown significant progress in neoadjuvant treatment, although the underlying mechanisms remain unclear. This study aimed to explore the reasons for the enhanced efficacy of T+AI from a pathological perspective in the context of HCC.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on 49 patients with HCC who were treated with T before surgical resection. Twenty-three patients received T+AI, while 26 received only T. Immunohistochemistry was performed to evaluate clinical data, including disease-free survival. Immune cells were recorded based on 4 methods, including tumor-infiltrating lymphocyte (TIL) percentage (the percentage of positive lymphocytes in the central area of the tumor) and the other 3 methods. Blood vessels were classified on the basis of the presence of VETC (vessels that encapsulate tumor clusters).</p><p><strong>Results: </strong>The group analysis results suggested that disease-free survival in the T+AI group was significantly better than that in the T group. Analysis revealed that CD8+TILs were a prognostic factor for neoadjuvant treatment and lower carbonic anhydrase 9 and VETC positivity in the T+AI group, with significant differences in immune cell infiltration and vascular classification. VETC positivity was associated with higher residual tumor rates and lower CD8+TIL levels.</p><p><strong>Conclusions: </strong>Pathological assessment of CD8+TILs in cancer tissues may serve as an important indicator for evaluating the efficacy of neoadjuvant therapy in HCC. The presence of VETC and carbonic anhydrase 9 may also affect the efficacy of neoadjuvant therapy and could potentially serve as indicators.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid β-oxidation enhances immune regulatory function of double-negative T cells through pSTAT4-OX40 signaling pathway.","authors":"Zeyu Wang, Yuan Jiang, Longyang Zhou, Xinjie Zhong, Jingjing Zhu, Jie Sun, Xiaotong Han, Hua Jin, Dong Zhang, Guangyong Sun","doi":"10.1097/HC9.0000000000000783","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000783","url":null,"abstract":"<p><strong>Background: </strong>Double-negative T (DNT) cells (CD3+CD4-CD8-NK1.1-) demonstrate immunoregulatory functions in maintaining hepatic immune homeostasis. This study investigates how energy metabolism impacts DNT cell survival and immunoregulatory functions, exploring potential therapeutic applications for autoimmune hepatitis.</p><p><strong>Methods: </strong>We compared DNT cells with conventional CD4+ T cells through lipidomic analysis, fatty acid β-oxidation (FAO) assessment, and single-cell RNA sequencing. Cells were treated with fatty acids (oleic acid and palmitic acid) and the FAO inhibitor Etomoxir (Eto). We evaluated cell survival, proliferation, and function through flow cytometry and reverse transcription-quantitative polymerase chain reaction. Transcriptome sequencing identified key regulatory molecules. The therapeutic potential was assessed in a Concanavalin A (ConA)-induced autoimmune hepatitis mouse model receiving DNT and DNT-Eto cell treatments.</p><p><strong>Results: </strong>DNT cells showed higher fatty acid content, FAO levels, and related gene expression compared with CD4+ T cells. Fatty acid supplementation enhanced DNT cell proliferation and immunoregulatory function, whereas FAO inhibition significantly impaired cell survival and function. Transcriptome analysis identified OX40 as a key regulator of DNT cell survival and function, regulated by FAO-activated pSTAT4. In the ConA-induced murine model, therapeutic administration of DNT cells significantly ameliorated the severity of autoimmune hepatitis compared with the ConA-treated control group. Meanwhile, DNT-Eto-treated groups showed more severe liver injury and elevated liver enzymes compared with DNT-treated groups. In vivo analyses revealed that DNT cells exhibited superior survival, function, and CD4+ T cell inhibition compared with Eto-treated or OX40 KO-DNT cells.</p><p><strong>Conclusions: </strong>FAO regulates DNT cell survival and immunoregulatory function through the pSTAT4-OX40 pathway, enhancing their protective effect against autoimmune hepatitis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbon-ion radiotherapy achieves outcomes equivalent to surgical resection for hepatocellular carcinoma.","authors":"Takeshi Hatanaka, Kei Shibuya, Satoru Kakizaki, Atsushi Hiraoka, Toshifumi Tada, Kazuya Kariyama, Ei Itobayashi, Kunihiko Tsuji, Toru Ishikawa, Hidenori Toyoda, Yuichi Koshiyama, Atsushi Naganuma, Yuhei Miyasaka, Yuki Kanayama, Kazunari Tanaka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Shinichiro Nakamura, Takashi Kumada, Tatsuya Ohno","doi":"10.1097/HC9.0000000000000801","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000801","url":null,"abstract":"<p><strong>Aim: </strong>This study aimed to compare the clinical outcomes of carbon-ion radiotherapy (CIRT) to those of surgical resection (SR) in patients with HCC.</p><p><strong>Methods: </strong>This retrospective study included 116 and 947 patients initially receiving CIRT and SR in Japanese institutions from September 2010 and June 2022. We used inverse probability of treatment weighting (IPTW) analysis to correct for imbalances in baseline patient characteristics between the 2 groups.</p><p><strong>Results: </strong>The median observation period was 3.3 years (IQR: 1.4-5.8) in the SR group and 2.8 years (IQR: 1.6-4.5) in the CIRT group (p=0.2). Before IPTW analysis, the median recurrence-free survival (RFS) was 2.3 years in the SR group and 2.2 years in the CIRT group, with no statistical significance (p=0.3). After IPTW analysis, the median RFS was 2.5 years in the SR group and 2.3 years in the CIRT group, which remained statistically nonsignificant (p=0.9). The median overall survival (OS) was not reached in the SR group, while it was 7.4 years in the CIRT group. The SR group demonstrated better survival compared to the CIRT group (p=0.02). In the IPTW cohort, the median OS was not reached in the SR group, while it remained 7.4 years in the CIRT group, showing no significant difference (p=0.4). Multivariate analyses showed that treatment choice (SR vs. CIRT) was not identified as a predictive factor for both RFS and OS.</p><p><strong>Conclusions: </strong>CIRT showed no statistically significant differences in RFS or OS compared with SR, suggesting its potential as a curative treatment option for early-stage HCC.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis.","authors":"Anne-Marie C Overstreet, McKenzie Burge, Annette Bellar, Megan R McMullen, Vartika Srivastava, Douglas Czarnecki, Emily Huang, Vai Pathak, Chelsea Finney, Raveena Vij, Kylee A Hunter, B Ben Koff, Srinivasan Dasarathy, Jaividhya Dasarathy, David Streem, Nicole Welch, Daniel Rotroff, Daniela Allende, Adam M Schmitt, Laura E Nagy, Jeannette S Messer","doi":"10.1097/HC9.0000000000000768","DOIUrl":"10.1097/HC9.0000000000000768","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 [Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27] is a DAMP released from stressed cells, including hepatocytes. The goal of this study was to define the role of HSPB1 in AH pathophysiology.</p><p><strong>Methods: </strong>Serum HSPB1 was measured in a retrospective study of 184 healthy controls (HCs), heavy alcohol consumers (HA), patients with alcohol-associated cirrhosis (AC), and patients with AH recruited from major hospital centers.HSPB1 was also evaluated in liver tissue from HC and AH patients, existing RNA-seq data from ALD patient liver and monocytes, and livers from mice fed a Lieber-DeCarli diet. Cellular models of hepatocyte and macrophage interactions were used to evaluate the role of HSPB1 in inflammation during AH.</p><p><strong>Results: </strong>Circulating HSPB1 was significantly increased in AH patients, and levels positively correlated with disease-severity scores. HSPB1 was also increased in the livers of patients with severe AH and ethanol-fed mice. In cellular models, ethanol-stressed hepatocytes released HSPB1, which then triggered TNFα-mediated inflammation in macrophages. Anti-HSPB1 antibody prevented TNFα release from macrophages exposed to media conditioned by ethanol-stressed hepatocytes.</p><p><strong>Conclusions: </strong>Our findings support investigation of HSPB1 as both a biomarker and therapeutic target in ALD. Furthermore, this work demonstrates that anti-HSPB1 antibody is a rational approach to targeting HSPB1 with the potential to block inflammation and protect hepatocytes, without inactivating host defense.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediterranean diet and associated metabolite signatures in relation to MASLD progression: A prospective cohort study.","authors":"Kai Wang, Shijian Xiang, Qiangsheng He, Anran Liu, Chumei Huang, Zhen Yang, Renjie Li, Jiaxin Hu, Ruisheng Cai, Ningning Mi, Zixin Liang, Zuofeng Xu, Jinqiu Yuan, Bin Xia","doi":"10.1097/HC9.0000000000000791","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000791","url":null,"abstract":"<p><strong>Background: </strong>Mediterranean diet (MED) is recommended for managing metabolic dysfunction-associated steatotic liver disease (MASLD). However, associations between MED adherence, related metabolite signatures, and risks of liver-related events (LRE) and mortality in MASLD patients remain unclear.</p><p><strong>Methods: </strong>We performed a prospective analysis using UK Biobank data, including 47,429 MASLD participants free of LRE at baseline. MED adherence was assessed as alternate Mediterranean Diet (aMED) score through a validated questionnaire. Metabolic biomarkers were measured using high-throughput nucleic magnetic resonance (NMR) spectroscopy. Cox regression and restricted cubic splines assessed the association of aMED, its components, with risk of LRE and mortality. Mediation analysis evaluated the role of metabolites in the relationship between aMED, its components, and MASLD progression.</p><p><strong>Results: </strong>Over a median follow-up of 13.3 years, 296 LRE cases and 3616 deaths occurred. Higher aMED scores (6-9) were associated with lower risks of LRE (HR: 0.553, 95% CI: 0.351-0.874) and mortality (HR: 0.854, 95% CI: 0.762-0.956) compared with the lowest scores (0-3), with linear dose-response relationships. Vegetables and legumes were associated with lower LRE risk, while vegetables, nuts, fish, MUFA:SFA ratio, and moderate alcohol intake were linked to reduced mortality. Of 143 metabolites, 46 were significantly associated with aMED. Omega-3 fatty acids, the omega-3 to total fatty acid ratio, and albumin accounted for 7.9%, 11.9%, and 2.6% of the reduction in LRE, and 19.4%, 23.1%, and 4.7% of the mitigation in mortality, respectively.</p><p><strong>Conclusions: </strong>Adherence to MED is linked to reduced LRE risk and mortality in MASLD patients. Metabolic biomarkers, particularly small HDL particles and omega-3 fatty acids, may mitigate MASLD progression.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arachidonic acid metabolism in metabolic dysfunction-associated steatotic liver disease and liver fibrosis.","authors":"Yufang Ma, Jingsun Jiang, Chong Zhao, Bo Wei, Jinhang Gao","doi":"10.1097/HC9.0000000000000802","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000802","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder globally, affecting 30% of the population and causing a significant healthcare burden due to its increasing incidence and limited therapeutic options. Arachidonic acid (AA) is a key bioactive lipid precursor that generates eicosanoids, such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acids, via 3 distinct enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P450. Emerging evidence indicates that AA-derived metabolites and pathway factors contribute to the progression and severity of MASLD and liver fibrosis. This review systematically summarizes the pathophysiological roles of AA metabolism in MASLD and liver fibrosis, focusing on mechanisms involving lipid accumulation, liver inflammation, fibrogenesis, and related cellular processes. In addition, we discuss potential therapeutic targets within the AA metabolic pathway in MASLD and liver fibrosis, highlighting emerging clinical advances targeting AA metabolites and pathway factors to improve these pathological conditions.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: Unifying FALD assessment-A call to arms.","authors":"Jae Hee Seol, Jin Young Song, Su Jin Kim, Hoon Ko, Jae Yoon Na, Min Jung Cho, Hee Jung Choi, Jue Seong Lee, Kyung Jin Oh, Se Yong Jung, Jo Won Jung","doi":"10.1097/HC9.0000000000000790","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000790","url":null,"abstract":"","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12384881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipocyte-specific deletion of gp130 prevents ketogenic diet-induced hepatic steatosis.","authors":"Berkay Senkalfa, Melanie Gloor, Ronja Podlaszewski, Revati S Dewal, Carla Horvath, Vissarion Efthymiou, Adhideb Ghosh, Stephan Wueest, Daniel Konrad, Christian Wolfrum, Tenagne D Challa","doi":"10.1097/HC9.0000000000000782","DOIUrl":"10.1097/HC9.0000000000000782","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes, can progress to metabolic dysfunction-associated steatohepatitis and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. The ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms.</p><p><strong>Methods and results: </strong>Herein, we investigated the mechanisms behind KD-induced metabolic dysfunction-associated steatohepatitis and fibrosis at thermoneutrality, identifying upregulated inflammatory and lipogenic pathways, including Il-6, Tnf, Mapk13, Lpl, and Pparg. Given the substantial increase in IL-6 during MASLD progression, we investigated IL-6-gp130 signaling using liver- and adipocyte-specific knockout mice. Liver-specific gp130 deletion failed to prevent KD-induced hepatic steatosis and glucose intolerance. In contrast, adipocyte-specific gp130 deletion significantly reduced KD-induced hepatic steatosis by suppressing lipolysis in white adipose tissue and reducing p-JNK and p-p38 signaling in the liver. In agreement, adipocyte-specific deletion of gp130 protected mice from KD-induced hepatic steatosis in response to recombinant IL-6 treatment.</p><p><strong>Conclusions: </strong>Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12385040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leukemia inhibitory factor promotes human cholangiopathies, and its inhibition improves cholestasis in Abcb4-/- mice.","authors":"Cristina Di Giorgio, Ginevra Urbani, Carmen Massa, Silvia Marchianò, Michele Biagioli, Martina Bordoni, Ginevra Lachi, Benedetta Sensini, Rachele Del Sordo, Francesca Paniconi, Eleonora Giannelli, Maria Rosaria Sette, Luigi Cari, Elva Morretta, Maria Chiara Monti, Rosa De Gregorio, Valentina Sepe, Angela Zampella, Ainhoa Lapitz, Piotr Milkiewicz, Malgorzata Milkiewicz, Jesus M Banales, Eleonora Distrutti, Stefano Fiorucci","doi":"10.1097/HC9.0000000000000779","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000779","url":null,"abstract":"<p><strong>Background: </strong>Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated cholestatic disorders characterized by progressive biliary inflammation and fibrosis, for which treatment options remain limited, underscoring the need for novel therapeutic targets. The leukemia inhibitory factor (LIF) is an IL-6-related cytokine that dysregulates the communication between epithelial cells and extracellular matrices by binding a heterodimeric complex formed by LIF receptor (LIFR) and gp130. The role of the LIF/LIFR system in PSC and PBC and its potential as a therapeutic target remain unclear.</p><p><strong>Methods: </strong>We investigated LIF/LIFR system alteration in PSC and PBC and assessed the therapeutic potential of LIFR antagonism in a genetic mouse model of PSC (Abcb4-/- mice). Single-cell transcriptomics analyses were performed to evaluate LIF and LIFR expression in human liver samples. Whole liver RNA-seq and immunostaining were used to assess LIF/LIFR levels and correlation with fibrotic and immune markers. The effects of LIFR antagonism were evaluated in vitro using LRI-310, a steroidal LIFR antagonist, on human cholangiocytes, HSCs, endothelial cells, and macrophages. In vivo, LRI-310 was administered to Abcb4-/- mice, and effects on liver injury, cholestasis, fibrosis, leukocyte infiltration, and gene expression were assessed.</p><p><strong>Results: </strong>LIF expression s enriched in human cholangiocytes, while LIFR is predominantly expressed by HSCs, endothelial cells, and macrophages. Whole liver RNAseq analysis and liver sections immunostaining demonstarted that increased LIF expression correlates with expression of markers of hepatic fibrosis and immune activation in PSC and PBC patients. LRI-310, a steroidal LIFR antagonist, attenuated human cholangiocytes activation and expression of inflammatory mediators, as well as the activation of liver sinusoidal cells and hepatic fibroblasts. In Abcb4-/- mice administration of LRI-310 mitigated liver injury, cholestasis, liver leukocytes infiltration and reduced the expression of biomarkers associated with fibrosis, inflammation, and bile acid dismetabolism.</p><p><strong>Conclusion: </strong>Cholangiocyte-derived LIF promotes the formation of a pro-inflammatory and pro-fibrotic niche centred on damaged cholangiocytes. LIFR antagonism reverses fibrosis and immune dysregulation in Abcb4-/- mice, supporting the development of anti-LIFR therapies in human cholangiopathies.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12385065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}