Targeting ADAR1-mediated RNA editing inhibits hepatic stellate cell activation and liver fibrosis by enhancing HSC-intrinsic IFN signaling

This study aims to characterize the RNA editome during fibrogenesis and to elucidate the role of ADAR1 in hepatic stellate cell (HSC) activation and liver fibrosis. We showed that ADAR1 ablation in primary mouse HSCs ameliorated HSC activation. Mechanistically, ADAR1 ablation led to dsRNA accumulation and activated HSC-intrinsic IFN signaling in an MDA5-dependent manner. RNA editome analysis revealed that the 3' UTR of the pro-fibrogenic gene Col3a1 was highly edited by ADAR1, leading to mRNA stabilization and increased protein expression. Targeting ADAR1-mediated RNA editing in HSCs holds promise to prevent and treat liver fibrosis. Overall design: Primary HSCs isolated from Adar1f/f/Cre-ER mice were treated with vehicle or 100 nM of 4-OHT to induce Adar1 ablation and culture-activated for 4 days.