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7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

Florencio Porto FreitasHamed AlborziniaAncély Ferreira Dos SantosPalina S NepachalovichLohans PedreraOmkar ZilkaAlex InagueCorinna KleinNesrine ArouaKamini KaushalBettina KastSvenja M LorenzViktoria KunzHelene NehringThamara Nishida Xavier da SilvaZhiyi ChenSena AticiSebastian G DollEmily L SchaeferIfedapo EkpoWerner SchmitzAline HorlingPeter ImmingSayuri MiyamotoAnn Marie WehmanThiago C Genaro-MattosKaroly MirnicsLokender KumarJudith Klein-SeetharamanSvenja MeierjohannIsabel WeigandMatthias KroissGeorg W BornkammFernando GomesLuis Eduardo Soares NettoManjima B SathianDavid B KonradDouglas F CoveyBernhard MichalkeKurt BommertRalf Christian BargouAna J Garcia-SaezDerek A PrattMaria FedorovaFlavia Carla MeottiMarcus ConradJosé Pedro Friedmann Angeli
Published in: Nature (2024)
Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation 1,2 . Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation 3 , we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
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