7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

• 成果类型: Article
• 署名作者: 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
• 署名单位: University of Wurzburg; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Technische Universitat Dresden; Carl Gustav Carus University Hospital; Technische Universitat Dresden; University of Cologne; University of Ottawa; Universidade de Sao Paulo; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Wurzburg; University of Wurzburg; Martin Luther University Halle Wittenberg; University of Denver; University of Nebraska System; University of Nebraska Medical Center; Shoolini University; Colorado School of Mines; Arizona State University; Arizona State University-Downtown Phoenix; University of Wurzburg; University of Munich; Ulm University; Universidade de Sao Paulo; University of Munich; Washington University (WUSTL); Washington University (WUSTL); Helmholtz Association; German Cancer Research Center (DKFZ)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5515
• DOI: 10.1038/s41586-023-06878-9
• 发表日期: 2024-02-08
• 关键词: therapeutic targets; lipid-peroxidation; oxysterols; mechanisms; oxidation; protects; sterols; reveals; cells; acsl4

摘要

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.