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

• Published in: Nature communications Vol. 15; no. 1; p. 2195
• Main Authors: Yamada, Naoya, Karasawa, Tadayoshi, Ito, Junya, Yamamuro, Daisuke, Morimoto, Kazushi, Nakamura, Toshitaka, Komada, Takanori, Baatarjav, Chintogtokh, Saimoto, Yuma, Jinnouchi, Yuka, Watanabe, Kazuhisa, Miura, Kouichi, Yahagi, Naoya, Nakagawa, Kiyotaka, Matsumura, Takayoshi, Yamada, Ken-ichi, Ishibashi, Shun, Sata, Naohiro, Conrad, Marcus, Takahashi, Masafumi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14/19; 38/43; 49/40; 631/80/82; 64/60; 692/4020/4021/288/2032; 692/699/1503/1607; 7-Dehydrocholesterol reductase; 82/1; 82/58; 82/80; Ablation; Acetaminophen; Animals; Biosynthesis; Cholesterol; Cyclodextrins; Electron paramagnetic resonance; Electron spin; Electron spin resonance; Electrons; Enzymes; Ferroptosis; Hepatocellular carcinoma; Hepatocytes; Humanities and Social Sciences; Humans; Injury prevention; Ischemia; Liver; Liver Diseases; Metabolites; Mice; multidisciplinary; Oxidation; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Pathophysiology; Reductases; Regulatory mechanisms (biology); Reperfusion; Science; Science (multidisciplinary); Spin resonance; Substrate inhibition; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; β-Cyclodextrin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46386-6

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. Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.