7-Dehydrocholesterol–Mediated Regulation of Ferroptosis in the Liver

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a critical role in liver diseases such as ischemia-reperfusion injury, drug-induced liver failure, and steatohepatitis. We recently identified 7-dehydrocholesterol reductase (DHCR7) as a novel regulator of hepatic ferroptosis through genome-wide CRISPR screening. Loss or inhibition of DHCR7 leads to intracellular accumulation of its substrate, 7-dehydrocholesterol (7-DHC), which exhibits strong radical-trapping activity. 7-DHC sacrificially reacts with lipid radicals, thereby protecting polyunsaturated phospholipids from peroxidation and suppressing ferroptosis. In vitro, DHCR7 inhibition or exogenous 7-DHC addition reduced ferroptotic cell death, while in vivo, Dhcr7 deficiency or pharmacologic blockade ameliorated liver injury in mouse models of hepatic ischemia-reperfusion and acetaminophen toxicity. These findings establish the DHCR7/7-DHC axis as a liver-specific regulatory pathway of ferroptosis, conferring protection to normal hepatocytes yet potentially promoting resistance in cancer cells. This context-dependent dual effect may provide a foundation for disease-tailored therapeutic strategies.

graphical abstract