Activation of lysosomal iron triggers ferroptosis in cancer PMID: 40335696

ADC Targets in Oncology

2026-04-10

Activation of lysosomal iron triggers ferroptosis in cancer

Nature. 2025 Jun;642(8067):492-500. doi: 10.1038/s41586-025-08974-4.

Tatiana Cañeque ^# ¹ , Leeroy Baron ^# ¹ , Sebastian Müller ^# ¹ , Alanis Carmona ² , Ludovic Colombeau ¹ , Antoine Versini ¹ , Stéphanie Solier ¹ ³ ⁴ , Christine Gaillet ¹ , Fabien Sindikubwabo ¹ , Julio L Sampaio ¹ , Marie Sabatier ² , Eikan Mishima ⁵ , Armel Picard-Bernes ¹ , Laurène Syx ⁶ , Nicolas Servant ⁶ , Bérangère Lombard ⁷ , Damarys Loew ⁷ , Jiashuo Zheng ⁵ , Bettina Proneth ⁵ , Leishemba K Thoidingjam ¹ , Laurence Grimaud ⁸ , Cameron S Fraser ² , Krystina J Szylo ² , Emma Der Kazarian ⁹ , Caroline Bonnet ⁹ , Emmanuelle Charafe-Jauffret ⁹ , Christophe Ginestier ⁹ , Patricia Santofimia-Castaño ¹⁰ , Matias Estaras ¹⁰ , Nelson Dusetti ¹⁰ , Juan Lucio Iovanna ¹⁰ , Antonio Sa Cunha ¹¹ , Gabriella Pittau ¹¹ , Pascal Hammel ¹¹ , Dimitri Tzanis ¹² , Sylvie Bonvalot ¹² , Sarah Watson ¹³ , Vincent Gandon ¹⁴ , Aditya Upadhyay ¹⁵ , Derek A Pratt ¹⁵ , Florêncio Porto Freitas ¹⁶ , José Pedro Friedmann Angeli ¹⁶ , Brent R Stockwell ¹⁷ ¹⁸ ¹⁹ , Marcus Conrad ⁵ ²⁰ , Jessalyn M Ubellacker ² , Raphaël Rodriguez ²¹

Affiliations

1. Institut Curie, CNRS, INSERM, PSL Research University, Paris, France.
2. Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
3. Department of Genetics, Institut Curie, Paris, France.
4. Paris Saclay University, UVSQ, Montigny-le-Bretonneux, France.
5. Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany.
6. Institut Curie, INSERM, Mines Paris Tech, PSL Research University, Paris, France.
7. Institut Curie, PSL Research University, Paris, France.
8. Ecole Normale Supérieure, CNRS, PSL Research University, Paris, France.
9. CRCM, CNRS, INSERM, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
10. CRCM, CNRS, INSERM, Institut Paoli-Calmettes, Aix-Marseille University, Parc Scientifique et Technologique de Luminy, Marseille, France.
11. Department of Digestive and Medical Oncology, Paris Saclay University and Paul-Brousse Hospital (APHP Sud), Villejuif, France.
12. Department of Surgical Oncology, Institut Curie, Paris, France.
13. Department of Medical Oncology, Institut Curie, INSERM, PSL Research University, Paris, France.
14. Institut de Chimie Moléculaire et des Matériaux d'Orsay, CNRS, Paris Saclay University, Orsay, France.
15. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
16. Rudolf-Virchow-Zentrum, Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
17. Department of Chemistry, Columbia University, New York, NY, USA.
18. Department of Biological Sciences, Columbia University, New York, NY, USA.
19. Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
20. Translational Redox Biology, TUM Natural School of Sciences, Technical University of Munich, Garching, Germany.
21. Institut Curie, CNRS, INSERM, PSL Research University, Paris, France. [email protected].
# Contributed equally.

Abstract

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 Ferroptosis^2-4; 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 CD44^high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation^6,7 while conferring vulnerability to Ferroptosis^8,9. 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.