7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

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

• Document type: Journal article
• Source: Nature; v. 626, n. 7998, p. 33-pg., 2024-02-08.

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. 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. (AU)

• FAPESP's process: 17/13804-1 - Mechanisms of detoxification and repair of oxidized biological membranes involving the action of the enzyme peroxiredoxin 6
• Grantee: Alex Inague
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC