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Freitas, F.P.* ; Alborzinia, H.* ; Dos Santos, A.F.* ; Nepachalovich, P.* ; Pedrera, L.* ; Zilka, O.* ; Inague, A.* ; Klein, C.* ; Aroua, N.* ; Kaushal, K.* ; Kast, B.* ; Lorenz, S. ; Kunz, V.* ; Nehring, H.* ; Xavier da Silva, T.N.* ; Chen, Z.* ; Atici, S.* ; Doll, S. ; Schaefer, E.L.* ; Ekpo, I.* ; Schmitz, W.* ; Horling, A.* ; Imming, P.* ; Miyamoto, S.* ; Wehman, A.M.* ; Genaro-Mattos, T.C.* ; Mirnics, K.* ; Kumar, L.* ; Klein-Seetharaman, J.* ; Meierjohann, S.* ; Weigand, I.* ; Kroiss, M.* ; Bornkamm, G.W.* ; Gomes, F.* ; Netto, L.E.S.* ; Sathian, M.B.* ; Konrad, D.B.* ; Covey, D.F.* ; Michalke, B. ; Bommert, K.* ; Bargou, R.C.* ; García-Sáez, A.J.* ; Pratt, D.A.* ; Fedorova, M.* ; Trumpp, A.* ; Conrad, M. ; Friedmann Angeli, J.P.*

7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

Nature 626, 401-410 (2024)
Postprint DOI PMC
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Therapeutic Targets; Lipid-peroxidation; Oxysterols; Mechanisms; Oxidation; Protects; Sterols; Reveals; Cells; Acsl4
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 626, Heft: 7998, Seiten: 401-410 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Research Unit BioGeoChemistry and Analytics (BGC)
Förderungen Dietmar Hopp Foundation
Deutsche Krebshilfe
DKTK joint funding project 'RiskY-AML'
DFG
Deutsche Jose Carreras Leukamie Stiftung (DJCLS)
Interdisziplinares Zentrum fur klinische Forschung (IZKF)
DFG CRC205
Deutsche Forschungsgemeinschaft (DFG)
European Research Council (ERC)
German Federal Ministry of Education and Research (BMBF)

NIH
National Science Foundation
National Institutes of Health NIMH
Sao Paulo Research Foundation (FAPESP)
Fonds of the Chemical Industry for a Liebig fellowship
ERC
BMBF VIP+ program NEUROPROTEKT
Deutsche Forschungsgemeinschaft
Sachsische Aufbaubank
SMWK
Junior Group Leader programme of the Rudolf Virchow Center, University of Wurzburg