7-Dehydrocholesterol dictates ferroptosis sensitivity

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 and Ping Wang ()
Additional contact information
Yaxu Li: Tongji University
Qiao Ran: Tongji University
Qiuhui Duan: Tongji University
Jiali Jin: Tongji University
Yanjin Wang: Tongji University
Lei Yu: Tongji University
Chaojie Wang: Tongji University
Zhenyun Zhu: Chinese Academy of Sciences
Xin Chen: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Linjun Weng: Tongji University
Zan Li: Tongji University
Jia Wang: Tongji University
Qi Wu: Tongji University
Hui Wang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hongling Tian: Tongji University
Sihui Song: Tongji University
Zezhi Shan: Tongji University
Qiwei Zhai: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Huanlong Qin: Tongji University
Shili Chen: Shanghai Jiao Tong University School of Medicine
Lan Fang: Tongji University
Huiyong Yin: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hu Zhou: Chinese Academy of Sciences
Xuejun Jiang: Memorial Sloan-Kettering Cancer Center
Ping Wang: Tongji University

Nature, 2024, vol. 626, issue 7998, 411-418

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06983-9 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:626:y:2024:i:7998:d:10.1038_s41586-023-06983-9

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06983-9

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().