2. Academic Validation
  3. 7-Dehydrocholesterol dictates ferroptosis sensitivity

7-Dehydrocholesterol dictates ferroptosis sensitivity

  • Nature. 2024 Jan 31. doi: 10.1038/s41586-023-06983-9.
Yaxu Li # 1 2,  Qiao Ran # 1 2,  Qiuhui Duan # 1 2,  Jiali Jin # 1 2,  Yanjin Wang 1 2,  Lei Yu 1 2,  Chaojie Wang 1 2,  Zhenyun Zhu 3,  Xin Chen 4,  Linjun Weng 1 2,  Zan Li 1,  Jia Wang 1,  Qi Wu 1 2,  Hui Wang 5,  Hongling Tian 1,  Sihui Song 1 2,  Zezhi Shan 1,  Qiwei Zhai 5,  Huanlong Qin 1,  Shili Chen 6,  Lan Fang 1 2,  Huiyong Yin 4 7,  Hu Zhou 3,  Xuejun Jiang 8,  Ping Wang 9 10
Affiliations

Affiliations

  • 1 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, China.
  • 3 Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 6 Shanghai Key Laboratory of Biliary Tract Disease Research, Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
  • 8 Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 9 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China. wangp@tongji.edu.cn.
  • 10 Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, China. wangp@tongji.edu.cn.
  • # Contributed equally.
PMID: 38297130 DOI: 10.1038/s41586-023-06983-9
Abstract

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.

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