Xiang-Jie Zhu, Zhi Zhong, Jiang-Chuan Du, Jiu-Yu Zhang, Xu Zhang, Xiu-Liang Cui, Ling-Ting Guan, Yan-Yu Hu, Can Chen, Han Wang, Xiang-Yu Wu, Wei-Jia Zhang, Pei-Lin Zhang, Hong-Yang Wang
{"title":"通过TGF-β和GSK-3信号共同抑制原位肝星状细胞转化改善肝纤维化","authors":"Xiang-Jie Zhu, Zhi Zhong, Jiang-Chuan Du, Jiu-Yu Zhang, Xu Zhang, Xiu-Liang Cui, Ling-Ting Guan, Yan-Yu Hu, Can Chen, Han Wang, Xiang-Yu Wu, Wei-Jia Zhang, Pei-Lin Zhang, Hong-Yang Wang","doi":"10.1111/liv.70187","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background and Aims</h3>\n \n <p>Liver fibrosis, a progressive condition driven by chronic liver injury and excessive scar tissue formation, can lead to cirrhosis, a life-threatening disease. Activation of hepatic stellate cells (HSCs) is central to fibrosis progression, yet current therapies fail to halt or reverse this process. This study evaluated a combination therapy targeting HSCs to ameliorate fibrosis and promote liver repair.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>A small molecule cocktail, SBCH (SB431542, a TGF-β inhibitor, and CHIR99021, a GSK-3 inhibitor), was tested in three fibrosis models: CCl<sub>4</sub>-induced, bile duct ligation (BDL) and non-alcoholic steatohepatitis (NASH) with diethylnitrosamine (DEN). Therapeutic effects were assessed using phenotypic analyses, in vivo tracing and single-cell RNA sequencing to uncover mechanisms.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>SBCH significantly reduced fibrosis in all models by inhibiting HSC activation and fibrogenic activity. The suppression of PI3K/Akt pathway and EMT cascade contribute to the fibrosis-ameliorating effect of SBCH treatment. Furthermore, in vivo tracing and single-cell RNA sequencing revealed that SBCH induced the conversion of activated HSCs into hepatocyte-like cells (ciHeps), which integrated into liver tissue, repaired liver damage and restored liver integrity and function.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>SBCH mitigates liver fibrosis through multifaceted mechanisms, including the inhibition of HSC activation, suppression of fibrogenic activity and regulation of key signalling pathways such as PI3K/Akt and EMT. In addition, SBCH induces the trans-differentiation of activated HSCs into hepatocyte-like cells (ciHeps), effectively reducing pathogenic HSCs while increasing functional ciHeps. This dual-target approach not only facilitates liver tissue repair but also restores liver function, offering a promising therapeutic strategy for liver fibrosis and cirrhosis, with potential applications in conditions arising from various aetiologies of liver injury.</p>\n </section>\n </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 7","pages":""},"PeriodicalIF":5.2000,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70187","citationCount":"0","resultStr":"{\"title\":\"Amelioration of Liver Fibrosis via In Situ Hepatic Stellate Cell Conversion Through Co-Inhibition of TGF-β and GSK-3 Signalling\",\"authors\":\"Xiang-Jie Zhu, Zhi Zhong, Jiang-Chuan Du, Jiu-Yu Zhang, Xu Zhang, Xiu-Liang Cui, Ling-Ting Guan, Yan-Yu Hu, Can Chen, Han Wang, Xiang-Yu Wu, Wei-Jia Zhang, Pei-Lin Zhang, Hong-Yang Wang\",\"doi\":\"10.1111/liv.70187\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background and Aims</h3>\\n \\n <p>Liver fibrosis, a progressive condition driven by chronic liver injury and excessive scar tissue formation, can lead to cirrhosis, a life-threatening disease. Activation of hepatic stellate cells (HSCs) is central to fibrosis progression, yet current therapies fail to halt or reverse this process. This study evaluated a combination therapy targeting HSCs to ameliorate fibrosis and promote liver repair.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>A small molecule cocktail, SBCH (SB431542, a TGF-β inhibitor, and CHIR99021, a GSK-3 inhibitor), was tested in three fibrosis models: CCl<sub>4</sub>-induced, bile duct ligation (BDL) and non-alcoholic steatohepatitis (NASH) with diethylnitrosamine (DEN). Therapeutic effects were assessed using phenotypic analyses, in vivo tracing and single-cell RNA sequencing to uncover mechanisms.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>SBCH significantly reduced fibrosis in all models by inhibiting HSC activation and fibrogenic activity. The suppression of PI3K/Akt pathway and EMT cascade contribute to the fibrosis-ameliorating effect of SBCH treatment. Furthermore, in vivo tracing and single-cell RNA sequencing revealed that SBCH induced the conversion of activated HSCs into hepatocyte-like cells (ciHeps), which integrated into liver tissue, repaired liver damage and restored liver integrity and function.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>SBCH mitigates liver fibrosis through multifaceted mechanisms, including the inhibition of HSC activation, suppression of fibrogenic activity and regulation of key signalling pathways such as PI3K/Akt and EMT. In addition, SBCH induces the trans-differentiation of activated HSCs into hepatocyte-like cells (ciHeps), effectively reducing pathogenic HSCs while increasing functional ciHeps. This dual-target approach not only facilitates liver tissue repair but also restores liver function, offering a promising therapeutic strategy for liver fibrosis and cirrhosis, with potential applications in conditions arising from various aetiologies of liver injury.</p>\\n </section>\\n </div>\",\"PeriodicalId\":18101,\"journal\":{\"name\":\"Liver International\",\"volume\":\"45 7\",\"pages\":\"\"},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2025-06-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70187\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Liver International\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/liv.70187\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Liver International","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/liv.70187","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Amelioration of Liver Fibrosis via In Situ Hepatic Stellate Cell Conversion Through Co-Inhibition of TGF-β and GSK-3 Signalling
Background and Aims
Liver fibrosis, a progressive condition driven by chronic liver injury and excessive scar tissue formation, can lead to cirrhosis, a life-threatening disease. Activation of hepatic stellate cells (HSCs) is central to fibrosis progression, yet current therapies fail to halt or reverse this process. This study evaluated a combination therapy targeting HSCs to ameliorate fibrosis and promote liver repair.
Methods
A small molecule cocktail, SBCH (SB431542, a TGF-β inhibitor, and CHIR99021, a GSK-3 inhibitor), was tested in three fibrosis models: CCl4-induced, bile duct ligation (BDL) and non-alcoholic steatohepatitis (NASH) with diethylnitrosamine (DEN). Therapeutic effects were assessed using phenotypic analyses, in vivo tracing and single-cell RNA sequencing to uncover mechanisms.
Results
SBCH significantly reduced fibrosis in all models by inhibiting HSC activation and fibrogenic activity. The suppression of PI3K/Akt pathway and EMT cascade contribute to the fibrosis-ameliorating effect of SBCH treatment. Furthermore, in vivo tracing and single-cell RNA sequencing revealed that SBCH induced the conversion of activated HSCs into hepatocyte-like cells (ciHeps), which integrated into liver tissue, repaired liver damage and restored liver integrity and function.
Conclusions
SBCH mitigates liver fibrosis through multifaceted mechanisms, including the inhibition of HSC activation, suppression of fibrogenic activity and regulation of key signalling pathways such as PI3K/Akt and EMT. In addition, SBCH induces the trans-differentiation of activated HSCs into hepatocyte-like cells (ciHeps), effectively reducing pathogenic HSCs while increasing functional ciHeps. This dual-target approach not only facilitates liver tissue repair but also restores liver function, offering a promising therapeutic strategy for liver fibrosis and cirrhosis, with potential applications in conditions arising from various aetiologies of liver injury.
期刊介绍：
Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
