Hepatic microRNA-320 restrains ferroptosis to mitigate acute-on-chronic alcohol-induced liver injury

Abstract

Alcohol-associated Liver Disease (ALD) is one of the major chronic liver diseases worldwide and has high mortality and high incidence rate. microRNA-320 (miR-320), a highly conserved and widely expressed miRNA, has been reported to be involved in lipid metabolism; however, whether miR-320 affects the progression of ALD remains unclear. In this study, we demonstrated that hepatic miR-320 was significantly downregulated in chronic-plus-binge alcohol-fed mice. Interestingly, such downregulation might accelerate ALD progression as evidenced that hepatocyte-specific miR-320 deficient mice displayed higher susceptibility to acute-on-chronic alcohol feeding-induced steatosis and inflammation. Moreover, restoration of hepatic miR-320 ameliorated acute-on-chronic alcohol-induced hepatocyte damage and steatosis. Mechanistically, miR-320 inhibited alcohol-induced ferroptosis by targeting Transferrin Receptor 1 (TFRC) to suppress iron accumulation. Moreover, silencing of Tfrc in hepatocytes attenuated ethanol-induced iron accumulation, thus inhibiting ferroptosis and ultimately mitigating ALD. Taken together, these findings suggest that miR-320 plays an important role in limiting ALD progression via inhibiting ferroptosis, providing a therapeutic target for the treatment of ALD.