7-Dehydrocholesterol dictates ferroptosis sensitivity
7-Dehydrocholesterol dictates ferroptosis sensitivity | |
Author | Li, YX; Ran, Q; Duan, QH; Jin, JL; Wang, YJ; Yu, L; Wang, CJ; Zhu, ZY; Chen, X; Weng, LJ; Li, Z; Wang, J; Wu, Q; Wang, H; Tian, HL; Song, SH; Shan, ZZ; Zhai, QW; Qin, HL; Chen, SL; Fang, L; Yin, HY; Zhou, H; Jiang, XJ; Wang, P |
Journal | NATURE |
Pub Year | 2024 |
Type | |
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. 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. |
Issue | 626 |
Volume | 626 |
SCI | 50.5 |