Targeting CFTR restoring aggrephagy to suppress HSC activation and alleviate liver fibrosis.

Background and Aims: 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.
Methods: 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 ₄ ) 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.
Result: 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.
Conclusion: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)