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

Naoya Yamada (), Tadayoshi Karasawa (), Junya Ito, Daisuke Yamamuro, Kazushi Morimoto, Toshitaka Nakamura, Takanori Komada, Chintogtokh Baatarjav, Yuma Saimoto, Yuka Jinnouchi, Kazuhisa Watanabe, Kouichi Miura, Naoya Yahagi, Kiyotaka Nakagawa, Takayoshi Matsumura, Ken-ichi Yamada, Shun Ishibashi, Naohiro Sata, Marcus Conrad and Masafumi Takahashi ()
Additional contact information
Naoya Yamada: Jichi Medical University
Tadayoshi Karasawa: Jichi Medical University
Junya Ito: Tohoku University
Daisuke Yamamuro: Jichi Medical University
Kazushi Morimoto: Kyushu University, Fukuoka
Toshitaka Nakamura: Molecular Target and Therapeutics Center, Helmholtz Munich
Takanori Komada: Jichi Medical University
Chintogtokh Baatarjav: Jichi Medical University
Yuma Saimoto: Kyushu University, Fukuoka
Yuka Jinnouchi: Kyushu University, Fukuoka
Kazuhisa Watanabe: Jichi Medical University
Kouichi Miura: Jichi Medical University
Naoya Yahagi: Jichi Medical University
Kiyotaka Nakagawa: Tohoku University
Takayoshi Matsumura: Jichi Medical University
Ken-ichi Yamada: Kyushu University, Fukuoka
Shun Ishibashi: Jichi Medical University
Naohiro Sata: Jichi Medical University
Marcus Conrad: Molecular Target and Therapeutics Center, Helmholtz Munich
Masafumi Takahashi: Jichi Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46386-6

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