7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

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.

On the Products of Cholesterol Autoxidation in Phospholipid Bilayers and the Formation of Secosterols Derived Therefrom.

In homogenous solution, cholesterol autoxidation leads to a mixture of epimers of 5 primary products, whose concentrations vary in the presence/absence of antioxidants, such as vitamin E. Two of the products (5α-OOH and 6ß-OOH) undergo Hock fragmentation to yield electrophilic secosterols implicated in disease. Herein, we show that the product distribution is similar in phospholipid bilayers, in that the 7-OOHs are the major products, but the presence/absence of vitamin E has no effect on the distribution. Cholesterol 7α-OOH, but not 7ß-OOH, undergoes Hock fragmentation to yield a mixture of unprecedented A-ring cleavage products and 6,7-epoxides. When subjected to typical derivatization conditions, 7α-OOH yields products with essentially indistinguishable chromatographic and spectroscopic features from the previously identified secosterols, casting further doubt on their controversial origin from endogenous O3 .