Liver International最新文献

{"title":"Risk of Serious Bacterial and Non-Bacterial Infections in People With MASLD","authors":"Giovanni Targher,&nbsp;Herbert Tilg,&nbsp;Luca Valenti","doi":"10.1111/liv.70059","DOIUrl":"https://doi.org/10.1111/liv.70059","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease globally. MASLD is a multisystem disease where metabolic dysfunction plays a key role in the development of MASLD and its most relevant liver-related morbidities and extrahepatic complications, such as cardiovascular disease, chronic kidney disease and certain types of extrahepatic cancers. Among the least examined MASLD-related extrahepatic complications, an ever-increasing number of observational studies have reported a positive association between MASLD and the risk of serious bacterial infections (SBI) requiring hospital admission. This risk remained significant in those studies where statistical analysis was adjusted for age, sex, ethnicity, obesity, type 2 diabetes and other common comorbidities. Notably, the incidence rates of SBI were further increased with more advanced MASLD, especially in patients with MASLD-related cirrhosis, and were also observed for some acute viral infections, including SARS-CoV-2 infection, leading to severe COVID-19. In this narrative review article, we provide an overview of the literature on (a) the recent epidemiological data linking MASLD to the risk of serious bacterial and non-bacterial infections requiring hospital admission, (b) the putative underlying mechanisms through which MASLD may increase the susceptibility to serious infections, both directly and through the immune dysfunction associated with cirrhosis and portal hypertension, and (c) the practical and clinical implications of the increased risk of serious bacterial and non-bacterial infections in the growing global population with MASLD.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602683","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":"Use of Proton Pump Inhibitors Among Patients With Alcohol-Related Cirrhosis—A Danish Nationwide Cohort Study","authors":"Marine Sølling Ramsing,&nbsp;Morten Daniel Jensen,&nbsp;Peter Jepsen","doi":"10.1111/liv.70061","DOIUrl":"https://doi.org/10.1111/liv.70061","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Use of proton pump inhibitors (PPIs) may have adverse effects in patients with alcohol-related cirrhosis (ALD cirrhosis), but PPIs continue to be used by many patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>We aimed to describe the prevalence and incidence of PPI use from filled prescriptions among patients with ALD cirrhosis and to identify predictors of PPI initiation after ALD cirrhosis diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used Danish nationwide healthcare registries to investigate PPI use among patients diagnosed with ALD cirrhosis from 1997 to 2022. We used multivariable Cox regression to identify predictors of PPI initiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 41 263 patients diagnosed with ALD cirrhosis in 1997–2022. In this cohort, the prevalence of PPI use rose to 40% in 2016 and plateaued at this level through 2022. Considering time since diagnosis, 26% were using PPI at the diagnosis of ALD cirrhosis, and the prevalence peaked at 38% 3 months later. Among PPI users, 79% used more than 30 defined daily doses per year on average during the follow-up. Patients older than 50 years were more likely than younger patients to initiate PPI treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The use of PPIs continues to be prevalent among patients with ALD cirrhosis, with 40% of all patients using PPIs in 2022. Within the first 3 months after diagnosis, 38% of all patients were using PPIs. Our results provide essential background information for future RCTs on the risks and benefits of prescribing or deprescribing PPIs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595077","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":"A Markov Model Unveiling the Impact of Resmetirom on the Natural History of MASLD Patients: A Sistematic Review and Meta-Analysis","authors":"Grazia Pennisi,&nbsp;Gabriele Di Maria,&nbsp;Marco Enea,&nbsp;Marco Vaccaro,&nbsp;Ciro Celsa,&nbsp;Michela Antonucci,&nbsp;Giacinta Ciancimino,&nbsp;Carlo Ciccioli,&nbsp;Giuseppe Infantino,&nbsp;Claudia La Mantia,&nbsp;Adele Tulone,&nbsp;Vito Di Marco,&nbsp;Calogero Cammà,&nbsp;Salvatore Petta","doi":"10.1111/liv.70056","DOIUrl":"https://doi.org/10.1111/liv.70056","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aim</h3>\u0000 \u0000 <p>The MAESTRO-NASH phase 3 trial reported that a 52-week treatment of Resmetirom is effective in improving fibrosis and metabolic dysfunction-associated steatohepatitis (MASH) in patients with MASH and F2 or F3 fibrosis, while data on the impact on 5-year and long-term clinical outcomes are still lacking. We simulated the transition probabilities of disease progression in MASLD patients with F2 or F3 fibrosis and the effect of Resmetirom treatment on clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A meta-analysis of literature data formed transition matrices for fibrosis stages and complications, defined as compensated (CC) and decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and mortality—liver-related mortality (LR-M), cardiovascular mortality (CV-M) and extra-hepatic cancer mortality (EHC-M). Markov model was developed to depict the F2 and F3 fibrosis stage progression towards the complications and to evaluate the effect of Resmetirom treatment on the natural history of MASLD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We estimated the 5-year probability of Resmetirom-treated and untreated MASLD patients with baseline F2 fibrosis of developing CC (5.16% vs. 6.82%, respectively), DC (0.25% vs. 0.3%, respectively), HCC (0.25% vs. 0.32%, respectively) and mortality (0.15% vs. 0.16% for LR-M; 1.02% vs. 1.1% for CV-M; 1.07% vs. 1.2% for EHC-M, respectively). Similarly, we estimated the five-year probability of Resmetirom-treated and untreated MASLD patients with baseline F3 fibrosis of developing CC (17.12% vs. 21.34%, respectively), DC(1.1% vs. 1.47%, respectively), HCC (1.21% vs. 1.73%, respectively) and mortality (0.59% vs. 0.91% for LR-M, 1.92% vs. 2.14% for CV-M and 1.04% vs. 1.14% for EHC-M, respectively). Life Years Gained (LYG) of Resmetirom-treated patients were 0.45 and 0.63 in MASLD patients with F2 and F3 fibrosis, respectively, and the model was sensitive to changes in Resmetirom efficacy and transition probabilities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Resmetirom decreases the 5-year and lifetime Markov-model estimated risk of CC, DC, HCC and liver-related mortality in patients with MASLD and F2 or F3 fibrosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595078","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":"Global Burden of Major Chronic Liver Diseases in 2021","authors":"Gong Feng,&nbsp;Yusuf Yilmaz,&nbsp;Luca Valenti,&nbsp;Wai-Kay Seto,&nbsp;Calvin Q. Pan,&nbsp;Nahum Méndez-Sánchez,&nbsp;Feng Ye,&nbsp;Silvia Sookoian,&nbsp;Giovanni Targher,&nbsp;Christopher D. Byrne,&nbsp;Wah-Kheong Chan,&nbsp;Sombat Treeprasertsuk,&nbsp;Hon Ho Yu,&nbsp;Seung Up Kim,&nbsp;Jacob George,&nbsp;Wen-Jing Xu,&nbsp;Giada Sebastiani,&nbsp;Ponsiano Ocama,&nbsp;John D. Ryan,&nbsp;Monica Lupșor-Platon,&nbsp;Hasmik Ghazinyan,&nbsp;Saeed Hamid,&nbsp;Nilanka Perera,&nbsp;Khalid Alswat,&nbsp;Vasily Isakov,&nbsp;Qiuwei Pan,&nbsp;Shiv Kumar Sarin,&nbsp;Jörn M. Schattenberg,&nbsp;Mohammadjavad Sotoudeheian,&nbsp;Yu Jun Wong,&nbsp;Ala I. Sharara,&nbsp;Said A. Al-Busafi,&nbsp;Christopher Kenneth Opio,&nbsp;Jin Chai,&nbsp;Yasser Fouad,&nbsp;Yu Shi,&nbsp;Mamun Al-Mahtab,&nbsp;Sujuan Zhang,&nbsp;Carlos Jose Pirola,&nbsp;Vincent Wai-Sun Wong,&nbsp;Ming-Hua Zheng","doi":"10.1111/liv.70058","DOIUrl":"https://doi.org/10.1111/liv.70058","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study utilised the Global Burden of Disease data (2010–2021) to analyse the rates and trends in point prevalence, annual incidence and years lived with disability (YLDs) for major chronic liver diseases, such as hepatitis B, hepatitis C, metabolic dysfunction-associated liver disease, cirrhosis and other chronic liver diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Age-standardised rates per 100,000 population for prevalence, annual incidence and YLDs were compared across regions and countries, as well as the socio-demographic index (SDI). Trends were expressed as percentage changes (PC) and estimates were reported with uncertainty intervals (UI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Globally, in 2021, the age-standardised rates per 100,000 population for the prevalence of hepatitis B, hepatitis C, MASLD and cirrhosis and other chronic liver diseases were 3583.6 (95%UI 3293.6–3887.7), 1717.8 (1385.5–2075.3), 15018.1 (13756.5–16361.4) and 20302.6 (18845.2–21791.9) respectively. From 2010 to 2021, the PC in age-standardised prevalence rates were−20.4% for hepatitis B, −5.1% for hepatitis C, +11.2% for MASLD and + 2.6% for cirrhosis and other chronic liver diseases. Over the same period, the PC in age-standardized incidence rates were -24.7%, -6.8%, +3.2%, and +3.0%, respectively. Generally, negative associations, but with fluctuations, were found between age-standardised prevalence rates for hepatitis B, hepatitis C, cirrhosis and other chronic liver diseases and the SDI at a global level. However, MASLD prevalence peaked at moderate SDI levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The global burden of chronic liver diseases remains substantial. Hepatitis B and C have decreased in prevalence and incidence in the last decade, while MASLD, cirrhosis and other chronic liver diseases have increased, necessitating targeted public health strategies and resource allocation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing the Understanding of Obesity and Liver Health: Addressing Lifestyle, Socio-economic and Ethnic Disparities","authors":"Zeping Chen,&nbsp;Lincheng Duan,&nbsp;Changhu Sun","doi":"10.1111/liv.70035","DOIUrl":"https://doi.org/10.1111/liv.70035","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing MASLD Screening: Long-Term Management and Accuracy Challenges","authors":"Jianyu Lv,&nbsp;Yuxuan Chen,&nbsp;Junbin Yan","doi":"10.1111/liv.16140","DOIUrl":"https://doi.org/10.1111/liv.16140","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DRD2-Mediated AMPK Ubiquitination Regulates the Occurrence of Hepatic Steatosis","authors":"Peng Ma,&nbsp;Hao Ou,&nbsp;Junze Cai,&nbsp;Yuanli Zhang,&nbsp;Yu Ou","doi":"10.1111/liv.70053","DOIUrl":"https://doi.org/10.1111/liv.70053","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background &amp; Aims</h3>\u0000 \u0000 <p>G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Function of PNPLA3 I148M—Lessons From In Vivo Studies in Humans","authors":"Hannele Yki-Järvinen,&nbsp;Panu K. Luukkonen","doi":"10.1111/liv.70047","DOIUrl":"https://doi.org/10.1111/liv.70047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Steatotic liver disease (SLD) associated with insulin resistance (IR) and the metabolic syndrome (‘IR-SLD’) increases the risk of liver disease, type 2 diabetes and cardiovascular disease (CVD). SLD associated with the PNPLA3 I148M variant (‘PNPLA3-SLD’) also predisposes individuals to liver disease but protects against type 2 diabetes and CVD. Although in real life the two causes of SLD commonly co-exist, the opposite effects of ‘IR-SLD’ and ‘PNPLA3-SLD’ on CVD and liver disease suggest their pathogenesis differs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>This review summarises human data comparing the effects of ‘IR-SLD’ and ‘PNPLA3-SLD’ on the human liver lipidome, hepatic handling of fatty acids, pathways of intrahepatocellular triglyceride synthesis, circulating lipids and lipoproteins and adipose tissue inflammation. We also discuss how steatosis in PNPLA3 I148M carriers leads to defects in mitochondrial function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565216","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":"TMEM115 as an Oncogenic and Immunological Biomarker in Hepatocellular Carcinoma","authors":"Pingping Sun,&nbsp;Haiyan Xu,&nbsp;Chengfeng Guo,&nbsp;Lei Yang,&nbsp;Xiaojing Zhang,&nbsp;Bing Lu,&nbsp;Lei Chen,&nbsp;Jianfei Huang","doi":"10.1111/liv.70048","DOIUrl":"https://doi.org/10.1111/liv.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Transmembrane (TMEM) proteins are involved in fundamental biological processes such as material transport and signal transduction. TMEM115 is a member of the TMEM protein family, but its significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigate the clinical predictive significance and potential functions of TMEM115 in HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatics was used to investigate TMEM115 mRNA expression and immune infiltration score. Through multiplex immunohistochemistry analysis, we assessed its protein expression and association with HCC patient clinical features, prognosis and immune cell infiltration in HCC. Through in vitro and in vivo experiments, we evaluated the biological functions of TMEM115 in HCC cells and its impact on the immune microenvironment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TMEM115 mRNA and protein levels were significantly higher in HCC tissues compared to paracancerous liver tissues. Its protein expression correlated with clinical characteristics and overall survival in HCC patients. In HCC tissues, higher TMEM115 protein expression corresponded to lower proportions of CD66b⁺ neutrophils and CD8⁺ T cells and a higher proportion of CD4⁺ T cells. Furthermore, patients with low TMEM115 expression displayed higher programmed cell death ligand-1 and lower lymphocyte activation gene 3 protein expression. Functionally, TMEM115 knockdown inhibited the proliferation, migration and invasion of HCC cells. In orthotopic models, TMEM115 knockdown inhibited the growth of HCC and affected the infiltration of immune cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings show TMEM115 as a promising prognostic indicator for HCC and hold promise in predicting responses to immune therapy, emphasising its potential clinical relevance and intricate involvement in the immune microenvironment of HCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of MALT1 Protease Attenuates Hepatic Sinusoidal Obstruction Syndrome by Modulating NRF2/HO1 and NF-κB Pathway","authors":"Nidhi Sharma,&nbsp;Yogesh Chandra,&nbsp;Sai Balaji Andugulapati","doi":"10.1111/liv.70050","DOIUrl":"https://doi.org/10.1111/liv.70050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Hepatic sinusoidal obstruction syndrome (HSOS) is a rare liver disorder with potentially life-threatening consequences for colorectal chemotherapy and haematopoietic stem cell transplant recipients. MALT1 (mucous-associated lymphoid tissue lymphoma translocation protein-1) is a protein that plays a key role in the production of inflammatory cytokines, ischemia, atherosclerosis, apoptosis and thromboinflammation; however, its role in HSOS is largely unknown. We aimed to investigate the effect of MALT-1 inhibition in in vitro and in vivo models of HSOS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Two mouse models (FOLFOX challenge in immunocompetent and immunocompromised mice) were used to investigate the therapeutic benefits of the MALT-1 inhibitor (MI-2) in vivo. HHSEC, HLEC and RAW-264.7 cells served as in vitro models. HSOS-responsible genes, marker levels and downstream signalling were examined using quantitative real-time PCR, western blot, immunocytochemistry and immunohistochemistry analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In the current investigation, MI-2 significantly reduced FOLFOX-induced HSOS in both mouse models by inhibiting the occlusion of sinusoids, RBC extravasation and bridging fibrosis in liver sections. MI-2 treatment also dramatically reduced specific SOS markers (vWF, VEGF, ephrin, bilirubin and PECAM) and other inflammatory markers. Mechanistic investigation in in vitro models using macrophages, sinusoidal and endothelial cells demonstrated that MI-2 treatment significantly diminished the inflammatory marker levels/expression by lowering ROS production. In addition to the pharmacological approach, siRNA-mediated MALT1 suppression remarkably reduced chemokine and cytokine marker expression in sinusoidal cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Thus, our findings demonstrate that MALT1 suppression dramatically reduces FOLFOX-induced inflammatory and fibrotic conditions by modulating the NF-κB activation, paving the way for innovative HSOS therapy approaches.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}