7-Dehydrocholesterol dictates ferroptosis sensitivity

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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Author(s)

  • Yaxu Li
  • Qiao Ran
  • Qiuhui Duan
  • Jiali Jin
  • Yanjing 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
  • Shilin Chen
  • Lan Fang
  • Hu Zhou
  • Xuejun Jiang
  • Ping Wang

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)411–418
Journal / PublicationNature
Volume626
Issue number7998
Online published31 Jan 2024
Publication statusPublished - 8 Feb 2024

Link(s)

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 MSMO1CYP51A1, 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. © The Author(s), under exclusive licence to Springer Nature Limited 2024

Citation Format(s)

7-Dehydrocholesterol dictates ferroptosis sensitivity. / Li, Yaxu; Ran, Qiao; Duan, Qiuhui et al.
In: Nature, Vol. 626, No. 7998, 08.02.2024, p. 411–418.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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