7-Dehydrocholesterol dictates ferroptosis sensitivity
Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review
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Original language | English |
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Pages (from-to) | 411–418 |
Journal / Publication | Nature |
Volume | 626 |
Issue number | 7998 |
Online published | 31 Jan 2024 |
Publication status | Published - 8 Feb 2024 |
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Link to Scopus | https://www.scopus.com/record/display.uri?eid=2-s2.0-85183936646&origin=recordpage |
Permanent Link | https://scholars.cityu.edu.hk/en/publications/publication(bb55954f-619d-4097-93df-d67d3fc2a5cb).html |
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. © The Author(s), under exclusive licence to Springer Nature Limited 2024
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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.
In: Nature, Vol. 626, No. 7998, 08.02.2024, p. 411–418.
Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review
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