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Cañeque, T.* ; Baron, L.* ; Müller, S.* ; Carmona, A.* ; Colombeau, L.* ; Versini, A.* ; Solier, S.* ; Gaillet, C.* ; Sindikubwabo, F.* ; Sampaio, J.L.* ; Sabatier, M.* ; Mishima, E. ; Picard-Bernes, A.* ; Syx, L.* ; Servant, N.* ; Lombard, B.* ; Loew, D.* ; Zheng, J. ; Proneth, B. ; Thoidingjam, L.K.* ; Grimaud, L.* ; Fraser, C.S.* ; Szylo, K.J.* ; Der Kazarian, E.* ; Bonnet, C.* ; Charafe-Jauffret, E.* ; Ginestier, C.* ; Santofimia-Castaño, P.* ; Estaras, M.* ; Dusetti, N.* ; Iovanna, J.L.* ; Cunha, A.S.* ; Pittau, G.* ; Hammel, P.* ; Tzanis, D.* ; Bonvalot, S.* ; Watson, S.* ; Gandon, V.* ; Upadhyay, A.* ; Pratt, D.A.* ; Freitas, F.P.* ; Friedmann Angeli, J.P.* ; Stockwell, B.R.* ; Conrad, M. ; Ubellacker, J.M.* ; Rodriguez, R.*

Activation of lysosomal iron triggers ferroptosis in cancer.

Nature, DOI: 10.1038/s41586-025-08974-4 (2025)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Lipid-peroxidation; Cells; Addiction; Regulator; Damage; Dna
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Förderungen INSERM
Deutsche Forschungsgemeinschaft (DFG)
CNRS
Agence Nationale de la Recherche
Institut National du Cancer
Fondation Bettencourt Schueller
Klaus Grohe Foundation
Fondation pour la Recherche Mdicale
Ligue Contre le Cancer
German Federal Ministry of Education and Research (BMBF) VIP+ programme NEUROPROTEKT
BMBF programme FERROPATH
European Union (ERC-Consolidator)
INCa
ITMO Cancer of Aviesan
IPGP multidisciplinary program PARI
Natural Sciences and Engineering Research Council of Canada
Landry Cancer Biology Research Fellowship - NIH NIDDK
Ludwig Center at Harvard
Breast Cancer Alliance Young Investigator Grant
Deutsche Jose Carreras Leukmie Stiftung
Horizon Europe ERC
European Research Council under the European Union