Pub Date : 2025-12-01DOI: 10.1016/j.livres.2025.04.006
Chao Wang , Mingming Fan , Jianrong Liu , Xiaolu Guo , Zhipeng Tan , Xueying Huang , Zhuoran Li , Xiaomei Liu , Ye Zhang , Jianqi Feng , Rui Fang , Li Wang , Qiong Ke
Background and aims
Adeno-associated virus (AAV) is becoming an attractive vector due to its low toxicity and minimal immunogenicity. However, liver-targeted AAV gene therapy still faces challenges, such as low delivery efficiency and safety risks associated with high vector doses. Isolated hepatic perfusion (IHP) has been explored as a localized drug delivery method, yet its full potential in gene therapy remains under investigation. Here, we investigated the efficiency of AAV8 delivery via the IHP route and its preference for hepatic transduction.
Methods
The IHP route was established through surgery in rats and cynomolgus monkey, and the AAV8-dTomato solution was injected into the entire liver through the inflow tract and maintained for 10 min. One week later, liver tissues were obtained, and the dTomato fluorescence expression area fraction and intensity were analyzed.
Results
AAV8-dTomato delivery via the IHP resulted in over 60% dTomato-positive areas in rat liver and showed higher efficiency than the portal vein (PV) and inferior vena cava (IVC) routes at equivalent doses. In rats, AAV8-dTomato expression was primarily periportal across IHP, PV, and IVC routes, while in cynomolgus monkey, IHP delivery showed a pericentral pattern.
Conclusions
In this study, we found that IHP is an effective strategy for AAV8 delivery. In addition, the distribution characteristics of AAV8, when delivered in cynomolgus monkey via IHP, provide candidate vector delivery schemes for gene therapy for different types of genetic liver diseases.
{"title":"Efficient AAV8 delivery to the liver via isolated hepatic perfusion and analysis of hepatic lobule transduction patterns","authors":"Chao Wang , Mingming Fan , Jianrong Liu , Xiaolu Guo , Zhipeng Tan , Xueying Huang , Zhuoran Li , Xiaomei Liu , Ye Zhang , Jianqi Feng , Rui Fang , Li Wang , Qiong Ke","doi":"10.1016/j.livres.2025.04.006","DOIUrl":"10.1016/j.livres.2025.04.006","url":null,"abstract":"<div><h3>Background and aims</h3><div>Adeno-associated virus (AAV) is becoming an attractive vector due to its low toxicity and minimal immunogenicity. However, liver-targeted AAV gene therapy still faces challenges, such as low delivery efficiency and safety risks associated with high vector doses. Isolated hepatic perfusion (IHP) has been explored as a localized drug delivery method, yet its full potential in gene therapy remains under investigation. Here, we investigated the efficiency of AAV8 delivery via the IHP route and its preference for hepatic transduction.</div></div><div><h3>Methods</h3><div>The IHP route was established through surgery in rats and cynomolgus monkey, and the AAV8-dTomato solution was injected into the entire liver through the inflow tract and maintained for 10 min. One week later, liver tissues were obtained, and the dTomato fluorescence expression area fraction and intensity were analyzed.</div></div><div><h3>Results</h3><div>AAV8-dTomato delivery via the IHP resulted in over 60% dTomato-positive areas in rat liver and showed higher efficiency than the portal vein (PV) and inferior vena cava (IVC) routes at equivalent doses. In rats, AAV8-dTomato expression was primarily periportal across IHP, PV, and IVC routes, while in cynomolgus monkey, IHP delivery showed a pericentral pattern.</div></div><div><h3>Conclusions</h3><div>In this study, we found that IHP is an effective strategy for AAV8 delivery. In addition, the distribution characteristics of AAV8, when delivered in cynomolgus monkey via IHP, provide candidate vector delivery schemes for gene therapy for different types of genetic liver diseases.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 4","pages":"Pages 313-323"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.livres.2025.09.002
Linlin Ma , Shuzhen Chen , Hongyang Wang , Lei Chen
Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC), which is the predominant liver cancer type in Southeast Asia. Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide. HBV promotes HCC development through direct and indirect mechanisms. HBV DNA integrates into the host genome during the initial stages of tumorigenesis, causing insertional mutagenesis of cancer-related genes and genomic instability. Extrachromosomal circular DNA (ecDNA) is formed, which is efficiently amplified in large quantities to express viral genes and host oncogenes. Moreover, virus-associated proteins, such as the regulatory HBV X (HBx) protein and/or the modified preS/S envelope protein, alter the expression of genes associated with multiple functions in host cells. In this review, we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis. In addition to summarizing the specific mechanism of HBV-related tumorigenesis, the concerns and perspectives for future study are discussed.
乙型肝炎病毒（HBV）是导致肝细胞癌（HCC）的最常见原因，HCC是东南亚主要的肝癌类型。全世界约有3.5亿人患有持续性乙型肝炎感染。HBV通过直接和间接机制促进HCC的发展。在肿瘤发生的初始阶段，HBV DNA整合到宿主基因组中，导致癌症相关基因的插入突变和基因组不稳定。形成染色体外环状DNA (ecDNA)，其被大量高效扩增以表达病毒基因和宿主癌基因。此外，病毒相关蛋白，如HBV X （HBx）调节蛋白和/或修饰的preS/S包膜蛋白，可以改变宿主细胞中与多种功能相关的基因的表达。本文就HBx和preS/S蛋白在促进肿瘤发生中的作用进行综述。总结了hbv相关肿瘤发生的具体机制，并讨论了今后研究的问题和展望。
{"title":"Hepatitis B virus integration and hepatocarcinogenesis","authors":"Linlin Ma , Shuzhen Chen , Hongyang Wang , Lei Chen","doi":"10.1016/j.livres.2025.09.002","DOIUrl":"10.1016/j.livres.2025.09.002","url":null,"abstract":"<div><div>Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC), which is the predominant liver cancer type in Southeast Asia. Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide. HBV promotes HCC development through direct and indirect mechanisms. HBV DNA integrates into the host genome during the initial stages of tumorigenesis, causing insertional mutagenesis of cancer-related genes and genomic instability. Extrachromosomal circular DNA (ecDNA) is formed, which is efficiently amplified in large quantities to express viral genes and host oncogenes. Moreover, virus-associated proteins, such as the regulatory HBV X (HBx) protein and/or the modified preS/S envelope protein, alter the expression of genes associated with multiple functions in host cells. In this review, we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis. In addition to summarizing the specific mechanism of HBV-related tumorigenesis, the concerns and perspectives for future study are discussed.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 189-198"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.livres.2025.08.002
Jinfen Wang , Siwei Tan , Ruiying Zheng , Bilun Ke , Bin Wu , Manli Wu
Background and aims
Noninvasive assessments play a crucial role in ruling out high-risk esophageal varices (HREV) in cirrhotic patients. However, the value of sound touch elastography (STE) in predicting HREV has not been comprehensively investigated. Therefore, this study aimed to establish prediction models based on liver and spleen stiffness measurements obtained by STE and provide assessment strategies and cutoff values tailored for different clinical situations.
Methods
This prospective study included cirrhotic patients who underwent esophagogastroduodenoscopy (EGD). Liver and spleen stiffness measurements by STE were performed within six months of EGD examination. Various prediction models and their corresponding cutoff values were established for different clinical situations, incorporating spleen diameter and laboratory parameters.
Results
A total of 154 cirrhotic patients were included in the study and stratified into training (n = 119) and validation (n = 35) sets. Multivariable analysis revealed platelet, spleen diameter and spleen stiffness measurement as independent predictors of HREV. The model incorporating spleen stiffness measurement, platelet, and spleen diameter demonstrated superior performance in predicting HREV, yielding an area under the receiver operating characteristic curve (AUC) of 0.878 and 0.853 in the training set and validation set, respectively. Application of this model for screening cirrhotic patients could avoid EGDs in 39.7% (27/68) and 35.3% (6/17) of patients in the training and validation sets, respectively.
Conclusions
Liver and spleen stiffness measurements obtained through STE are valuable for predicting HREV in cirrhotic patients. The developed prediction models and their corresponding cutoff values provide tailored solutions for various clinical situations, thereby effectively reducing the need for unnecessary endoscopies.
{"title":"Noninvasive prediction of high-risk esophageal varices by spleen and liver stiffness measurements using sound touch elastography","authors":"Jinfen Wang , Siwei Tan , Ruiying Zheng , Bilun Ke , Bin Wu , Manli Wu","doi":"10.1016/j.livres.2025.08.002","DOIUrl":"10.1016/j.livres.2025.08.002","url":null,"abstract":"<div><h3>Background and aims</h3><div>Noninvasive assessments play a crucial role in ruling out high-risk esophageal varices (HREV) in cirrhotic patients. However, the value of sound touch elastography (STE) in predicting HREV has not been comprehensively investigated. Therefore, this study aimed to establish prediction models based on liver and spleen stiffness measurements obtained by STE and provide assessment strategies and cutoff values tailored for different clinical situations.</div></div><div><h3>Methods</h3><div>This prospective study included cirrhotic patients who underwent esophagogastroduodenoscopy (EGD). Liver and spleen stiffness measurements by STE were performed within six months of EGD examination. Various prediction models and their corresponding cutoff values were established for different clinical situations, incorporating spleen diameter and laboratory parameters.</div></div><div><h3>Results</h3><div>A total of 154 cirrhotic patients were included in the study and stratified into training (<em>n</em> = 119) and validation (<em>n</em> = 35) sets. Multivariable analysis revealed platelet, spleen diameter and spleen stiffness measurement as independent predictors of HREV. The model incorporating spleen stiffness measurement, platelet, and spleen diameter demonstrated superior performance in predicting HREV, yielding an area under the receiver operating characteristic curve (AUC) of 0.878 and 0.853 in the training set and validation set, respectively. Application of this model for screening cirrhotic patients could avoid EGDs in 39.7% (27/68) and 35.3% (6/17) of patients in the training and validation sets, respectively.</div></div><div><h3>Conclusions</h3><div>Liver and spleen stiffness measurements obtained through STE are valuable for predicting HREV in cirrhotic patients. The developed prediction models and their corresponding cutoff values provide tailored solutions for various clinical situations, thereby effectively reducing the need for unnecessary endoscopies.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 231-238"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.livres.2025.03.001
Li Pang , Leibo Xu , Zhijun Chen , Yang Liu , Tao Ding , Yanfang Ye , Xinjun Lu , Guangxiang Gu , Haoming Lin , Wenrui Wu , Kwan Man , Chao Liu
<div><h3>Background and aims</h3><div>Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors (ICIs) to increased allograft rejection risk after liver transplantation (LT), a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists. This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.</div></div><div><h3>Methods</h3><div>This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma (HCC) between June 2019 and March 2023. The recipients were categorized into ICI (<em>n</em> = 35) and non-ICI (<em>n</em> = 86) exposure groups based on pretransplant ICI exposure. Demographics, clinical characteristics, and short-term outcomes were compared between the cohorts. Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival. Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.</div></div><div><h3>Results</h3><div>Recipients with or without ICI exposure exhibited comparable demographic baseline characteristics. The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups. Post-transplant infection incidence was 37.1% and 20.9% in the ICI and non-ICI groups, respectively (<em>P</em> = 0.064). Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group (22.9% <em>vs.</em> 5.8%, <em>P</em> = 0.015). The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group (14.3% <em>vs.</em> 2.3%, <em>P</em> = 0.034). Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality, with ICI exposure being an independent risk factor for allograft rejection. In recipients with ICI exposure, a shorter interval between ICIs and LT (washout period) was significantly associated with a higher allograft rejection risk, with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival (<em>P</em> = 0.0001). Moreover, in recipients with allograft rejection, the peripheral CD4<sup>+</sup>/CD8<sup>+</sup> T cell ratio was much lower in the ICI group than in the non-ICI group.</div></div><div><h3>Conclusions</h3><div>Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC. A ≤21-day washout period was significantly associated with allograft rejection. Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings, confirm causality, and establish standardized clinical guidelines for ICI use before transplantation.</div></div><div><h3>Trail registration</h3><div><span><span>Clinica
{"title":"Short-term prognosis of recipients with pretransplant exposure to immune checkpoint inhibitors after liver transplantation for hepatocellular carcinoma: A retrospective cohort study","authors":"Li Pang , Leibo Xu , Zhijun Chen , Yang Liu , Tao Ding , Yanfang Ye , Xinjun Lu , Guangxiang Gu , Haoming Lin , Wenrui Wu , Kwan Man , Chao Liu","doi":"10.1016/j.livres.2025.03.001","DOIUrl":"10.1016/j.livres.2025.03.001","url":null,"abstract":"<div><h3>Background and aims</h3><div>Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors (ICIs) to increased allograft rejection risk after liver transplantation (LT), a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists. This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.</div></div><div><h3>Methods</h3><div>This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma (HCC) between June 2019 and March 2023. The recipients were categorized into ICI (<em>n</em> = 35) and non-ICI (<em>n</em> = 86) exposure groups based on pretransplant ICI exposure. Demographics, clinical characteristics, and short-term outcomes were compared between the cohorts. Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival. Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.</div></div><div><h3>Results</h3><div>Recipients with or without ICI exposure exhibited comparable demographic baseline characteristics. The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups. Post-transplant infection incidence was 37.1% and 20.9% in the ICI and non-ICI groups, respectively (<em>P</em> = 0.064). Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group (22.9% <em>vs.</em> 5.8%, <em>P</em> = 0.015). The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group (14.3% <em>vs.</em> 2.3%, <em>P</em> = 0.034). Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality, with ICI exposure being an independent risk factor for allograft rejection. In recipients with ICI exposure, a shorter interval between ICIs and LT (washout period) was significantly associated with a higher allograft rejection risk, with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival (<em>P</em> = 0.0001). Moreover, in recipients with allograft rejection, the peripheral CD4<sup>+</sup>/CD8<sup>+</sup> T cell ratio was much lower in the ICI group than in the non-ICI group.</div></div><div><h3>Conclusions</h3><div>Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC. A ≤21-day washout period was significantly associated with allograft rejection. Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings, confirm causality, and establish standardized clinical guidelines for ICI use before transplantation.</div></div><div><h3>Trail registration</h3><div><span><span>Clinica","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 221-230"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The critical shortage of liver transplant donors necessitates innovative solutions, with xenotransplantation emerging as a promising alternative. Despite significant ethical, scientific, and practical challenges, recent advancements in liver xenotransplantation, particularly using pigs as donors for non-human primates (NHPs), have extended graft survival duration. However, life-threatening issues such as thrombocytopenia and coagulation disorders persist, limiting survival to under a month. Advances in genetic engineering have enabled the modification of pig genomes to match the human immune system better, targeting genes responsible for immune rejection and increasing compatibility. While these breakthroughs enhance the potential for human transplantation, the challenges of immune rejection and long-term functionality remain substantial. This review highlights recent progress in liver xenotransplantation from pigs to NHPs and explores the implications for potential human clinical application.
{"title":"Revolutionizing medicine: Exploring the breakthroughs in liver xenotransplantation","authors":"Mohamed El-Kassas , Walaa Abdelhamed , Khalid Al-Naamani","doi":"10.1016/j.livres.2025.08.001","DOIUrl":"10.1016/j.livres.2025.08.001","url":null,"abstract":"<div><div>The critical shortage of liver transplant donors necessitates innovative solutions, with xenotransplantation emerging as a promising alternative. Despite significant ethical, scientific, and practical challenges, recent advancements in liver xenotransplantation, particularly using pigs as donors for non-human primates (NHPs), have extended graft survival duration. However, life-threatening issues such as thrombocytopenia and coagulation disorders persist, limiting survival to under a month. Advances in genetic engineering have enabled the modification of pig genomes to match the human immune system better, targeting genes responsible for immune rejection and increasing compatibility. While these breakthroughs enhance the potential for human transplantation, the challenges of immune rejection and long-term functionality remain substantial. This review highlights recent progress in liver xenotransplantation from pigs to NHPs and explores the implications for potential human clinical application.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 199-208"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.livres.2025.09.001
Xiaohui Fang , Yang Zhang , Junyao Wang , Yu Zhang , Ziliang Ke , Yiken Lin , Fangyuan Cong , Feng Zhang , Jianhua Zhou , Huiting Su , Shan Cao , Yulan Liu , Jun Xu
Background and aims
Primary sclerosing cholangitis (PSC) is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options. The mechanisms underlying the development and progression of PSCs remain unclear. Liver X receptor beta (LXR-β) is recognized to modulate lipid metabolism and immune response, but its specific involvement in the PSC has not been elucidated. Here, we explored the role and mechanism of LXR-β in PSC induced by 3, 5-diethoxycarbonyl-1, 4-dihydro-2, 4, 6-collidine (DDC).
Methods
CRISPR-Cas9 technology was applied to generate Abcb4 (coding MDR2, next named as Mdr2), Nr1h2 (coding LXR-β, next named as Lxrβ), and Rag2 (coding RAG2) knockout mice. DDC was used to induce PSC. Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis. Flow cytometry was used to observe immune cell subsets.
Results
We observed a declining trend in hepatic Lxrβ in the PSC model. Unexpectedly, Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis. Concomitantly, assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2−/− DDC mice. However, Lxrβ depletion intensified DDC-induced PSC in the Rag2−/− mice, with more abundant infiltrative inflammatory cells and more severe liver fibrosis. Compared with Rag2−/− DDC mice, Lxrβ−/−Rag2−/− DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes. Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.
Conclusion
This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.
{"title":"Innate immune cell LXR-β deficiency exacerbates hepatic injury and fibrosis in murine models of primary sclerosing cholangitis","authors":"Xiaohui Fang , Yang Zhang , Junyao Wang , Yu Zhang , Ziliang Ke , Yiken Lin , Fangyuan Cong , Feng Zhang , Jianhua Zhou , Huiting Su , Shan Cao , Yulan Liu , Jun Xu","doi":"10.1016/j.livres.2025.09.001","DOIUrl":"10.1016/j.livres.2025.09.001","url":null,"abstract":"<div><h3>Background and aims</h3><div>Primary sclerosing cholangitis (PSC) is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options. The mechanisms underlying the development and progression of PSCs remain unclear. Liver X receptor beta (LXR-β) is recognized to modulate lipid metabolism and immune response, but its specific involvement in the PSC has not been elucidated. Here, we explored the role and mechanism of LXR-β in PSC induced by 3, 5-diethoxycarbonyl-1, 4-dihydro-2, 4, 6-collidine (DDC).</div></div><div><h3>Methods</h3><div>CRISPR-Cas9 technology was applied to generate <em>Abcb4</em> (coding MDR2, next named as <em>Mdr2</em>), <em>Nr1h2</em> (coding LXR-β, next named as <em>Lxrβ</em>), and <em>Rag2</em> (coding RAG2) knockout mice. DDC was used to induce PSC. Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis. Flow cytometry was used to observe immune cell subsets.</div></div><div><h3>Results</h3><div>We observed a declining trend in hepatic <em>Lxrβ</em> in the PSC model. Unexpectedly, <em>Lxrβ</em> knockout failed to modulate DDC-induced PSC pathogenesis. Concomitantly, assessment of the influence of <em>Rag2</em> deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the <em>Rag2</em><sup><em>−/−</em></sup> DDC mice. However, <em>Lxrβ</em> depletion intensified DDC-induced PSC in the <em>Rag2</em><sup><em>−/−</em></sup> mice, with more abundant infiltrative inflammatory cells and more severe liver fibrosis. Compared with <em>Rag2</em><sup><em>−/−</em></sup> DDC mice, <em>Lxrβ</em><sup><em>−/−</em></sup><em>Rag2</em><sup><em>−/−</em></sup> DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes. Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.</div></div><div><h3>Conclusion</h3><div>This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 239-248"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.livres.2025.05.001
Zhixian Zhu , Sen Liang , Nan Zhao , Huiling Zou , Liangjun Zhang , Xiaoxun Zhang , Jin Chai
Background and aims
Liver fibrosis is a prevalent pathological stage of various chronic liver diseases and has the potential to progress to liver cirrhosis and hepatocellular carcinoma. However, experimental models for in vivo research are limited. Unexpectedly, increased liver inflammation and fibrosis were previously observed in mice treated with aluminum adjuvant (commercial Imject Alum, a mixture of Al(OH)3 and Mg(OH)2). Our study aimed to reveal the pathogenesis and pathological features of Imject Alum-induced liver injury and evaluate its potential as an experimental model of fibrotic liver disease.
Methods and materials
C57BL/6J mice were randomly divided into the following four groups: (i) control group, which received phosphate-buffered saline injections on days 1, 12, 26, 40, and 54; (ii) Imject Alum (Al(OH)3 160 mg/kg) D26 group, which was administered with Imject Alum (Al(OH)3 160 mg/kg) on days 1, 12, and 26; (iii) Imject Alum (Al(OH)3 80 mg/kg) D54; and (iv) Imject Alum (Al(OH)3 160 mg/kg) D54 groups, which were treated with 80 mg/kg and 160 mg/kg of Imject Alum (Al(OH)3), respectively, on days 1, 12, 26, 40, and 54. All reagents were delivered by intraperitoneal injection. Serum biochemical parameters, liver pathology, and expression of genes related to inflammation and fibrogenesis were evaluated. Transcriptome sequencing was performed. The genetic characteristics of the Imject Alum-induced liver lesions in the existing fibrosis model and patients with cirrhosis were determined.
Results
Administration of Imject Alum (Al(OH)3 160 mg/kg) at certain points for 54 days led to extensive hepatic inflammation and fibrosis, accompanied by disturbed bile acid metabolism in mice. Moreover, Imject Alum aggravated liver inflammation and injury by activating the pyroptosis-related inflammasome pathway. Transcriptome analysis revealed that Imject Alum-induced liver lesions had differentially expressed genes that were significantly enriched in pathways related to inflammation, fibrogenesis, and multiple metabolic processes. Moreover, Imject Alum-induced liver lesions exhibited gene signatures similar to those of existing fibrosis models and patients with cirrhosis.
Conclusions
Aluminum adjuvant (Imject Alum; Al(OH)3 160 mg/kg) administration at certain points for 54 days resulted in notable liver injury, inflammation, and fibrosis. This model had similar gene expression characteristics with existing fibrosis models and liver samples from patients with cirrhosis. Overall, aluminum adjuvant (Imject Alum)-induced mouse model may be a novel approach for establishing a liver fibrosis animal model.
{"title":"Aluminum adjuvant promotes liver inflammation and fibrosis in mice: A novel approach to establish a liver fibrosis animal model","authors":"Zhixian Zhu , Sen Liang , Nan Zhao , Huiling Zou , Liangjun Zhang , Xiaoxun Zhang , Jin Chai","doi":"10.1016/j.livres.2025.05.001","DOIUrl":"10.1016/j.livres.2025.05.001","url":null,"abstract":"<div><h3>Background and aims</h3><div>Liver fibrosis is a prevalent pathological stage of various chronic liver diseases and has the potential to progress to liver cirrhosis and hepatocellular carcinoma. However, experimental models for <em>in vivo</em> research are limited. Unexpectedly, increased liver inflammation and fibrosis were previously observed in mice treated with aluminum adjuvant (commercial Imject Alum, a mixture of Al(OH)<sub>3</sub> and Mg(OH)<sub>2</sub>). Our study aimed to reveal the pathogenesis and pathological features of Imject Alum-induced liver injury and evaluate its potential as an experimental model of fibrotic liver disease.</div></div><div><h3>Methods and materials</h3><div>C57BL/6J mice were randomly divided into the following four groups: (i) control group, which received phosphate-buffered saline injections on days 1, 12, 26, 40, and 54; (ii) Imject Alum (Al(OH)<sub>3</sub> 160 mg/kg) D26 group, which was administered with Imject Alum (Al(OH)<sub>3</sub> 160 mg/kg) on days 1, 12, and 26; (iii) Imject Alum (Al(OH)<sub>3</sub> 80 mg/kg) D54; and (iv) Imject Alum (Al(OH)<sub>3</sub> 160 mg/kg) D54 groups, which were treated with 80 mg/kg and 160 mg/kg of Imject Alum (Al(OH)<sub>3</sub>), respectively, on days 1, 12, 26, 40, and 54. All reagents were delivered by intraperitoneal injection. Serum biochemical parameters, liver pathology, and expression of genes related to inflammation and fibrogenesis were evaluated. Transcriptome sequencing was performed. The genetic characteristics of the Imject Alum-induced liver lesions in the existing fibrosis model and patients with cirrhosis were determined.</div></div><div><h3>Results</h3><div>Administration of Imject Alum (Al(OH)<sub>3</sub> 160 mg/kg) at certain points for 54 days led to extensive hepatic inflammation and fibrosis, accompanied by disturbed bile acid metabolism in mice. Moreover, Imject Alum aggravated liver inflammation and injury by activating the pyroptosis-related inflammasome pathway. Transcriptome analysis revealed that Imject Alum-induced liver lesions had differentially expressed genes that were significantly enriched in pathways related to inflammation, fibrogenesis, and multiple metabolic processes. Moreover, Imject Alum-induced liver lesions exhibited gene signatures similar to those of existing fibrosis models and patients with cirrhosis.</div></div><div><h3>Conclusions</h3><div>Aluminum adjuvant (Imject Alum; Al(OH)<sub>3</sub> 160 mg/kg) administration at certain points for 54 days resulted in notable liver injury, inflammation, and fibrosis. This model had similar gene expression characteristics with existing fibrosis models and liver samples from patients with cirrhosis. Overall, aluminum adjuvant (Imject Alum)-induced mouse model may be a novel approach for establishing a liver fibrosis animal model.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 3","pages":"Pages 209-220"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.livres.2025.01.001
John Y.L. Chiang
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has rapidly increased world-wide to 30%, with increasing of type 2 diabetes (T2D) and obesity in last two decades. The spectrum of MASLD covers from simple hepatic steatosis to the progressive metabolic dysfunction-associated steatohepatitis (MASH) with or without fibrosis, cirrhosis and hepatocellular carcinoma. The MASLD symptoms include dyslipidemia, hyperglycemia, insulin resistance and obesity, the liver manifestations of metabolic syndrome. Treatment option for MASH fibrosis is limited. Since the discovery of bile acids as the endogenous ligands of farnesoid X receptor (FXR) in early 1990, bile acid and FXR based-drug therapies have been developed and tested in clinical trials for cholestatic liver diseases and MASH fibrosis. However, many of these drugs have unwanted side-effects and moderate efficacy in improving fibrosis. The US Food and Drug Administration has not approved any of bile acid- and FXR-based drugs for MASH fibrosis. Drug therapies alternative to bile acid derivatives for MASH have been in clinical trials. Recently, resmetirom, a liver-specific- and thyroid hormone receptor beta-selective agonist has been approved for MASH fibrosis. Glucagon-like peptide-1 receptor agonists also are in clinical trials for MASH. This review covers recent development of novel drug therapies for MASH fibrosis, T2D and obesity.
{"title":"New drug therapies for metabolic dysfunction-associated steatohepatitis","authors":"John Y.L. Chiang","doi":"10.1016/j.livres.2025.01.001","DOIUrl":"10.1016/j.livres.2025.01.001","url":null,"abstract":"<div><div>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has rapidly increased world-wide to 30%, with increasing of type 2 diabetes (T2D) and obesity in last two decades. The spectrum of MASLD covers from simple hepatic steatosis to the progressive metabolic dysfunction-associated steatohepatitis (MASH) with or without fibrosis, cirrhosis and hepatocellular carcinoma. The MASLD symptoms include dyslipidemia, hyperglycemia, insulin resistance and obesity, the liver manifestations of metabolic syndrome. Treatment option for MASH fibrosis is limited. Since the discovery of bile acids as the endogenous ligands of farnesoid X receptor (FXR) in early 1990, bile acid and FXR based-drug therapies have been developed and tested in clinical trials for cholestatic liver diseases and MASH fibrosis. However, many of these drugs have unwanted side-effects and moderate efficacy in improving fibrosis. The US Food and Drug Administration has not approved any of bile acid- and FXR-based drugs for MASH fibrosis. Drug therapies alternative to bile acid derivatives for MASH have been in clinical trials. Recently, resmetirom, a liver-specific- and thyroid hormone receptor beta-selective agonist has been approved for MASH fibrosis. Glucagon-like peptide-1 receptor agonists also are in clinical trials for MASH. This review covers recent development of novel drug therapies for MASH fibrosis, T2D and obesity.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 2","pages":"Pages 94-103"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.livres.2025.04.002
Sathiyamoorthy Padmanaban , Ji-Won Baek , Sai Sahithya Chamarthy , Saipriya Chandrasekaran , Antony V Samrot , Vijayakumar Gosu , In-Kyu Park , Kamalakannan Radhakrishnan , Don-Kyu Kim
The liver is pivotal in protein synthesis, glucose and lipid metabolism, and detoxification. However, the liver is susceptible to both acute and chronic disorders, with chronic conditions being fatal. Chronic liver diseases (CLDs), such as liver fibrosis, which usually represents the early manifestation of cirrhosis, primarily result from hepatitis B and C viruses infections, metabolic disorders, alcohol abuse, immune-mediated attacks, and cholestatic injury. The progression of liver fibrosis contributes to the development of cirrhosis, which can further lead to hepatocellular carcinoma, portal hypertension, hepatic decompensation, and hepatic encephalopathy. The extracellular matrix deposition over time leading the hepatocyte necrosis (cirrhosis) is the main structural feature of CLDs and may cause hepatic failure. Certain conditions, such as hepatitis and autoimmune diseases, may promote the rapid deterioration of liver function. Acute and chronic liver failure causes may vary, with early referral for liver transplantation improving the chance of recovery. The healthcare system need improvements to manage patients with non-alcoholic fatty liver disease and alcoholic fatty liver disease, as they have the potential to progress to cirrhosis. Both conditions involve the release of reactive oxygen species and damage-associated molecular patterns from cytokines, hepatic stellate cells, and hepatocyte autophagy, leading to prolonged inflammation. While various medications target fibrosis and liver damage, nanoparticle-based drug delivery systems offer additional promise by promoting faster liver regeneration. This review provides a comprehensive overview of the potential of nanoparticle systems as a future therapeutic approach for treating liver disorders.
{"title":"Nanoparticle-based therapeutic strategies for chronic liver diseases: Advances and insights","authors":"Sathiyamoorthy Padmanaban , Ji-Won Baek , Sai Sahithya Chamarthy , Saipriya Chandrasekaran , Antony V Samrot , Vijayakumar Gosu , In-Kyu Park , Kamalakannan Radhakrishnan , Don-Kyu Kim","doi":"10.1016/j.livres.2025.04.002","DOIUrl":"10.1016/j.livres.2025.04.002","url":null,"abstract":"<div><div>The liver is pivotal in protein synthesis, glucose and lipid metabolism, and detoxification. However, the liver is susceptible to both acute and chronic disorders, with chronic conditions being fatal. Chronic liver diseases (CLDs), such as liver fibrosis, which usually represents the early manifestation of cirrhosis, primarily result from hepatitis B and C viruses infections, metabolic disorders, alcohol abuse, immune-mediated attacks, and cholestatic injury. The progression of liver fibrosis contributes to the development of cirrhosis, which can further lead to hepatocellular carcinoma, portal hypertension, hepatic decompensation, and hepatic encephalopathy. The extracellular matrix deposition over time leading the hepatocyte necrosis (cirrhosis) is the main structural feature of CLDs and may cause hepatic failure. Certain conditions, such as hepatitis and autoimmune diseases, may promote the rapid deterioration of liver function. Acute and chronic liver failure causes may vary, with early referral for liver transplantation improving the chance of recovery. The healthcare system need improvements to manage patients with non-alcoholic fatty liver disease and alcoholic fatty liver disease, as they have the potential to progress to cirrhosis. Both conditions involve the release of reactive oxygen species and damage-associated molecular patterns from cytokines, hepatic stellate cells, and hepatocyte autophagy, leading to prolonged inflammation. While various medications target fibrosis and liver damage, nanoparticle-based drug delivery systems offer additional promise by promoting faster liver regeneration. This review provides a comprehensive overview of the potential of nanoparticle systems as a future therapeutic approach for treating liver disorders.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"9 2","pages":"Pages 104-117"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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