Amelioration of Liver Fibrosis via In Situ Hepatic Stellate Cell Conversion Through Co-Inhibition of TGF-β and GSK-3 Signalling

IF 5.2 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2025-06-27 DOI:10.1111/liv.70187

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":"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}

引用次数: 0

Abstract

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.

Abstract Image

查看原文本刊更多论文

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

背景和目的肝纤维化是一种由慢性肝损伤和过度瘢痕组织形成驱动的进行性疾病，可导致肝硬化，这是一种危及生命的疾病。肝星状细胞（hsc）的激活是纤维化进展的核心，但目前的治疗方法无法阻止或逆转这一过程。本研究评估了一种针对造血干细胞的联合治疗，以改善纤维化和促进肝脏修复。方法采用小分子鸡尾酒SBCH （TGF-β抑制剂SB431542和GSK-3抑制剂CHIR99021）对ccl4诱导的胆管结扎（BDL）和二乙基亚硝胺（DEN）非酒精性脂肪性肝炎（NASH） 3种纤维化模型进行检测。使用表型分析、体内追踪和单细胞RNA测序来评估治疗效果，以揭示机制。结果SBCH通过抑制HSC活化和纤维化活性，显著减轻了所有模型的纤维化。抑制PI3K/Akt通路和EMT级联有助于SBCH治疗的纤维化改善作用。此外，体内追踪和单细胞RNA测序显示，SBCH诱导活化的hsc转化为肝细胞样细胞（ciHeps），这些细胞整合到肝组织中，修复肝损伤，恢复肝脏完整性和功能。结论SBCH通过多种机制减轻肝纤维化，包括抑制HSC活化、抑制纤维化活性和调节关键信号通路如PI3K/Akt和EMT。此外，SBCH诱导活化的hsc向肝细胞样细胞（ciHeps）的反分化，有效减少致病性hsc，增加功能性ciHeps。这种双靶点方法不仅能促进肝组织修复，还能恢复肝功能，为肝纤维化和肝硬化提供了一种有前景的治疗策略，在各种病因引起的肝损伤中具有潜在的应用前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

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.