Cholesterol Mediated Ferroptosis Suppression Reveals Essential Roles of Coenzyme Q and Squalene

Overview

Journal Commun Biol

Specialty Biology

Date 2023 Nov 2

PMID 37914914

Authors

Qi Sun

Diming Liu

Weiwei Cui

Huimin Cheng

Lixia Huang

Ruihao Zhang

Junlian Gu

Shuo Liu

Xiao Zhuang

Yi Lu

Bo Chu

Jian Li

Affiliations

Soon will be listed here.

Abstract

Recent findings have shown that fatty acid metabolism is profoundly involved in ferroptosis. However, the role of cholesterol in this process remains incompletely understood. In this work, we show that modulating cholesterol levels changes vulnerability of cells to ferroptosis. Cholesterol alters metabolic flux of the mevalonate pathway by promoting Squalene Epoxidase (SQLE) degradation, a rate limiting step in cholesterol biosynthesis, thereby increasing both CoQ10 and squalene levels. Importantly, whereas inactivation of Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), the branch point of cholesterol biosynthesis pathway, exhibits minimal effect on ferroptosis, simultaneous inhibition of both CoQ10 and squalene biosynthesis completely abrogates the effect of cholesterol. Mouse models of ischemia-reperfusion and doxorubicin induced hepatoxicity confirm the protective role of cholesterol in ferroptosis. Our study elucidates a potential role of ferroptosis in diseases related to dysregulation of cholesterol metabolism and suggests a possible therapeutic target that involves ferroptotic cell death.

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