Hepatocytes specific regulation mechanism of ferroptosis and potential therapeutic strategy for liver diseases

Abstract

Ferroptosis is known to be implicated in various liver diseases; however, the liver-specific regulatory mechanism of ferroptosis is not fully understood. We identified 7-dehydrocholesterol reductase (DHCR7) as a novel regulator of ferroptosis in hepatocytes. DHCR7 inhibition suppressed ferroptosis in Huh-7 cells. The DHCR7 inhibition increased the accumulation of intracellular 7-dehydrocholesterol (7-DHC), a substrate for DHCR7, and extrinsic 7-DHC supplementation suppressed ferroptosis. We assessed that oxidation of 7-DHC compensatory prevents cellular membrane lipid peroxidation related to ferroptosis. DHCR7 inhibitor also suppressed ferroptosis in murine primary hepatocytes and hepatic ischemia-reperfusion injury in mice. These findings suggest that targeting DHCR7 is a potential therapeutic strategy for ferroptosis-related liver disease.