Journal Article

7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

Netto, Luis Eduardo Soares, Kast, Bettina, Alborzinia, Hamed, Klein-Seetharaman, Judith, Garcia-Saez, Ana, Meierjohann, Svenja, Schmitz, Werner, Genaro-Mattos, Thiago C., Fedorova, Maria, Nepachalovich, Palina, Mirnics, Karoly, Covey, Douglas F., Nehring, Helene, Chen, Zhiyi, Doll, Sebastian G., Kroiss, Matthias, Inague, Alex, Miyamoto, Sayuri, Zilka, Omkar, Lorenz, Svenja M., Pedrera, Lohans, Aroua, Nesrine, Weigand, Isabel, Atici, Sena, Horling, Aline, Kaushal, Kamini, Pratt, Derek A., dos Santos, Ancély Ferreira, Kunz, Viktoria, Michalke, Bernhard, Gomes, Fernando, Kumar, Lokender, Sathian, Manjima B., Bargou, Ralf C., Konrad, David B., Freitas, Florencio Porto, Conrad, Marcus, Wehman, Ann M., Bommert, Kurt, Trumpp, Andreas, Xavier da Silva, Thamara N., Bornkamm, Georg W., Ekpo, Ifedapo, Friedmann Angeli, José Pedro, Imming, Peter, Schaefer, Emily L., Klein, Corinna

2024

Overview

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. Proferroptotic activity of 7-dehydrocholesterol reductase is shown along with an unexpected prosurvival function of its substrate, 7-dehydrocholesterol, indicating a cell-intrinsic mechanism that could be used by cancer cells to protect phospholipids from oxidative damage and escape ferroptosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 631/67/2327 / 631/80/82 / 64/60 / 7-Dehydrocholesterol reductase / Accumulation / Animals / Autoxidation / Biosynthesis / Burkitt Lymphoma - metabolism / Burkitt Lymphoma - pathology / Burkitt's lymphoma / Cancer / Cell death / Cell Survival / Cholesterol / CRISPR / Cytotoxicity / Dehydrocholesterols - metabolism / Enzymes / Fatty acids / Ferroptosis / Free radicals / Genes / Humanities and Social Sciences / Humans / Lipid Peroxidation / Lipids / Lymphoma / multidisciplinary / Neoplasm Transplantation / Neuroblastoma / Neuroblastoma - metabolism / Neuroblastoma - pathology / Oxidation-Reduction / Peroxyl radicals / Phenotype / Phenotypes / Phospholipids / Propagation / Reductases / Reproducibility of Results / Science / Science (multidisciplinary) / Substrates / Tumors / Xenotransplantation