7-Dehydrocholesterol dictates ferroptosis sensitivity

• 成果类型: Article
• 署名作者: Li, Yaxu; Ran, Qiao; Duan, Qiuhui; Jin, Jiali; Wang, Yanjin; Yu, Lei; Wang, Chaojie; Zhu, Zhenyun; Chen, Xin; Weng, Linjun; Li, Zan; Wang, Jia; Wu, Qi; Wang, Hui; Tian, Hongling; Song, Sihui; Shan, Zezhi; Zhai, Qiwei; Qin, Huanlong; Chen, Shili; Fang, Lan; Yin, Huiyong; Zhou, Hu; Jiang, Xuejun; Wang, Ping
• 署名单位: Tongji University; Tongji University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; Shanghai Institute of Nutrition & Health, CAS; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; University of Chinese Academy of Sciences, CAS; Shanghai Jiao Tong University; City University of Hong Kong; Memorial Sloan Kettering Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6870
• DOI: 10.1038/s41586-023-06983-9
• 发表日期: 2024-02-08
• 关键词: polyunsaturated fatty-acids; lemli-opitz-syndrome; cell-death; rate constants; cancer-cells; peroxidation; mechanisms; sterols; identification; pathogenesis

摘要

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. 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. 7-Dehydrocholesterol (7-DHC) is a natural anti-ferroptotic metabolite and pharmacological manipulation of 7-DHC levels shows promise as a therapeutic strategy for cancer and ischaemia-reperfusion injury.