Zhang Lu, Huang Wei, Ma Tao, Shi Xiang, Chen Jing, Hu Yi-Lin, Liu Yong-Xia, Liu Zhao-Xiu, Lu Cui-Hua
Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China.
Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China.
Int Immunopharmacol. 2025 Jan 3;145:113754. doi: 10.1016/j.intimp.2024.113754. Epub 2024 Dec 12.
Multiple studies have shown that hepatic fibrosis, a progressive condition that represents the endpoint of various chronic liver diseases, is primarily marked by the extensive activation of hepatic stellate cells (HSCs). However, the exact impact of cystic fibrosis transmembrane conductance regulator (CFTR) on HSCs during the development of hepatic fibrosis remains unclear.
In our study, we measured CFTR levels in tissue samples and in HSCs activated by TGF-β stimulation. We established mouse models of liver fibrosis using carbon tetrachloride (CCl) and bile duct ligation (BDL). In vitro, we investigated the specific mechanisms of CFTR action in HSCs by exploring aggrephagy. We employed co-immunoprecipitation (co-IP) experiments to identify potential downstream targets of CFTR. Finally, through rescue experiments, we examined the impact of GTPase-activating protein - binding protein 1 (G3BP1) on CFTR-mediated activation of hepatic stellate cells.
In activated HSCs induced by TGF-β, the reduction of CFTR, various liver fibrosis models, and fibrotic tissue samples were identified. In vitro functional experiments confirmed that CFTR promoted the expression of fibrosis-related markers and aggrephagy in HSCs. Mechanistically, we found that CFTR directly interacts with G3BP1, thereby further promoting the TGF-β/Smad2/3 pathway. The inhibition of G3BP1 caused by CFTR knockdown reduced extracellular matrix deposition, contributing to alleviating liver fibrosis.
We emphasize that CFTR activates aggrephagy and promotes HSC activation and hepatic fibrosis by targeting G3BP1, participating in the TGF-β/Smad2/3 signaling pathway. Overall, CFTR has been identified as a potential therapeutic target for liver fibrosis.
多项研究表明，肝纤维化是各种慢性肝病的终末期进展性疾病，主要特征是肝星状细胞（HSC）的广泛激活。然而，在肝纤维化发展过程中，囊性纤维化跨膜传导调节因子（CFTR）对HSC的确切影响仍不清楚。
在我们的研究中，我们测量了组织样本和经转化生长因子-β（TGF-β）刺激激活的HSC中的CFTR水平。我们使用四氯化碳（CCl）和胆管结扎（BDL）建立了肝纤维化小鼠模型。在体外，我们通过探索聚集自噬研究了CFTR在HSC中的具体作用机制。我们采用免疫共沉淀（co-IP）实验来鉴定CFTR的潜在下游靶点。最后，通过挽救实验，我们研究了GTP酶激活蛋白结合蛋白1（G3BP1）对CFTR介导的肝星状细胞激活的影响。
在TGF-β诱导激活的HSC、各种肝纤维化模型和纤维化组织样本中，均发现CFTR水平降低。体外功能实验证实，CFTR促进了HSC中纤维化相关标志物的表达和聚集自噬。从机制上讲，我们发现CFTR直接与G3BP1相互作用，从而进一步促进TGF-β/Smad2/3信号通路。CFTR敲低导致的G3BP1抑制减少了细胞外基质沉积，有助于减轻肝纤维化。
我们强调，CFTR通过靶向G3BP1激活聚集自噬，促进HSC激活和肝纤维化，参与TGF-β/Smad2/3信号通路。总体而言，CFTR已被确定为肝纤维化的潜在治疗靶点。
