Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis

Abstract

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

PRDX6 dictates ferroptosis sensitivity by directing cellular selenium mobilization

“…Since GPX4 belongs to the selenoprotein family, which is characterized by proteins carrying at least one selenocysteine (Sec) usually in their active site, this residue is critical for enabling full GPX4 enzymatic activity and protection from peroxide-inducible, irreversible overoxidation and enzyme inactivation 12 . In addition to the GSH/GPX4 axis, a series of genetic screens have unveiled alternative ferroptosis surveillance systems, such as the NAD(P)H/ferroptosis suppressor protein-1 (FSP1)/ubiquinone or vitamin K system 13–15 , di-/tetrahydrobiopterin/GTP cyclohydrolase 1 (GCH1)/dihydrofolate reductase (DHFR) system 16,17 and 7-dihydrocholesterol reductase (DHCR7) 18–20 , that can act as backup systems for GPX4 at least in certain cellular contexts. Unlike GPX4, these systems protect against the lipid peroxidation chain reaction by reducing phospholipid peroxyl radicals to phospholipid hydroperoxides that require additional steps for their decomposition.…”

“…Earlier work suggested that genetic perturbation of PRDX6 renders cancer cells more vulnerable to ferroptosis 25–27 . In addition, PRDX6 has been repeatedly identified in genetic screens or gene cluster analyses aimed at identifying genes impinging on ferroptosis regulation 17,28 . However, the mechanisms by which PRDX6 modulate ferroptosis susceptibility or its impact on PLOOH reduction remain poorly understood.…”