Aryl Hydrocarbon Receptor Alleviates Hepatic Fibrosis by Inducing Hepatic Stellate Cell Ferroptosis.

Abstract

Liver injury-induced activation of hepatic stellate cells (HSCs) is a crucial step in the progression of liver fibrosis. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is highly expressed in the liver. However, the role of AHR in liver fibrosis remains controversial. Our study revealed that the nontoxic ligand YH439 directly activated the AHR and regulated the expression of multidrug-resistant protein 1 (Mrp1) in mouse hepatic stellate cells (mHSCs), thereby diminishing the antioxidant capacity of mHSCs by promoting GSH efflux, and specifically inducing mHSCs ferroptosis without affecting hepatocytes. In a chronic liver fibrosis model, YH439 activated AHR to promote mHSC ferroptosis without causing hepatocyte ferroptosis, thereby alleviating liver fibrosis. Conclusively, this study shows that AHR alleviates liver fibrosis in mice by selectively inducing mHSC ferroptosis without causing hepatocyte ferroptosis and suggests that AHR is a potential target for the treatment of liver fibrosis.