7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M. Lorenz, Viktoria Kunz, Helene Nehring, Thamara N. Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G. Doll, Emily L. Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M. Wehman, Thiago C. Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W. Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B. Sathian, David B. Konrad, Douglas F. Covey, Bernhard Michalke, Kurt Bommert, Ralf C. Bargou, Ana Garcia-Saez, Derek A. Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad and José Pedro Friedmann Angeli ()
Additional contact information
Florencio Porto Freitas: University of Würzburg
Hamed Alborzinia: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Ancély Ferreira dos Santos: University of Würzburg
Palina Nepachalovich: University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden
Lohans Pedrera: University of Cologne
Omkar Zilka: University of Ottawa
Alex Inague: University of Würzburg
Corinna Klein: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Nesrine Aroua: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Kamini Kaushal: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Bettina Kast: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Svenja M. Lorenz: Helmholtz Zentrum München
Viktoria Kunz: Universitätsklinikum Würzburg
Helene Nehring: University of Würzburg
Thamara N. Xavier da Silva: University of Würzburg
Zhiyi Chen: University of Würzburg
Sena Atici: University of Würzburg
Sebastian G. Doll: Helmholtz Zentrum München
Emily L. Schaefer: University of Ottawa
Ifedapo Ekpo: University of Ottawa
Werner Schmitz: University of Würzburg
Aline Horling: Martin Luther University Halle Wittenberg
Peter Imming: Martin Luther University Halle Wittenberg
Sayuri Miyamoto: Universidade de Sao Paulo
Ann M. Wehman: University of Denver
Thiago C. Genaro-Mattos: University of Nebraska Medical Center
Karoly Mirnics: University of Nebraska Medical Center
Lokender Kumar: Shoolini University
Judith Klein-Seetharaman: Colorado School of Mines
Svenja Meierjohann: University of Würzburg
Isabel Weigand: Ludwig Maximillian University
Matthias Kroiss: Ludwig Maximillian University
Georg W. Bornkamm: University Hospital Ulm
Fernando Gomes: Universidade de São Paulo
Luis Eduardo Soares Netto: Universidade de São Paulo
Manjima B. Sathian: Ludwig Maximilian University of Munich
David B. Konrad: Ludwig Maximilian University of Munich
Douglas F. Covey: Washington University in St. Louis
Bernhard Michalke: Helmholtz Center München (HMGU)
Kurt Bommert: Universitätsklinikum Würzburg
Ralf C. Bargou: Universitätsklinikum Würzburg
Ana Garcia-Saez: University of Cologne
Derek A. Pratt: University of Ottawa
Maria Fedorova: University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden
Andreas Trumpp: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Marcus Conrad: Helmholtz Zentrum München
José Pedro Friedmann Angeli: University of Würzburg

Nature, 2024, vol. 626, issue 7998, 401-410

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06878-9

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