7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
Nature
; 626(7998): 401-410, 2024 Feb.
Article
in En
| MEDLINE
| ID: mdl-38297129
ABSTRACT
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 oxidation1,2. 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 peroxidation3, 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.
Full text:
1
Database:
MEDLINE
Main subject:
Burkitt Lymphoma
/
Dehydrocholesterols
/
Ferroptosis
/
Neuroblastoma
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nature
/
Nature (Lond.)
/
Nature (London)
Year:
2024
Type:
Article
Affiliation country:
Germany