7-Dehydrocholesterol Dictates Ferroptosis Sensitivity

Overview

Journal Nature

Specialty Science

Date 2024 Jan 31

PMID 38297130

Authors

Yaxu Li

Qiao Ran

Qiuhui Duan

Jiali Jin

Yanjin Wang

Lei Yu

Chaojie Wang

Zhenyun Zhu

Xin Chen

Linjun Weng

Zan Li

Jia Wang

Qi Wu

Hui Wang

Hongling Tian

Sihui Song

Zezhi Shan

Qiwei Zhai

Huanlong Qin

Shili Chen

Lan Fang

Huiyong Yin

Hu Zhou

Xuejun Jiang

Ping Wang

Affiliations

Soon will be listed here.

Abstract

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer, degenerative disorders and organ ischaemia-reperfusion injury (IRI). Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.

Citing Articles

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