Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability PMID: 42032311

ADC Targets in Oncology

2026-04-10

Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability

Nat Cell Biol. 2026 May;28(5):915-929. doi: 10.1038/s41556-026-01921-z.

Mariantonietta D'Ambrosio ¹ ² , Matthew E H White ¹ ³ ⁴ , Efthymios S Gavriil ³ , Laura Bousset ¹ ² , Jodie Birch ¹ ² , Aleksandra Gruevska ⁵ , Emiliano Pasquini ⁶ ⁷ , Manuel Colucci ⁶ ⁷ , Winnie Fong ⁸ ⁹ , Simone Mosole ⁶ ⁷ , Aurora Valdata ⁶ ⁷ ¹⁰ , Dimitris Veroutis ¹¹ , Katie Tyson ¹² , Vikas Ranvir ⁹ , Sandra Prokosch ⁹ , Joaquim Pombo ¹ ² , Aoki Ardisson ³ , Sanjay Khadayate ¹ ² , George Young ¹ ² , Alex Montoya ¹ ² , Georgia Roumelioti ¹ ² , Jack Houghton ³ , Jianan Lu ³ , Pavel V Shliaha ¹ ² , Elena De Vita ³ ¹³ , Santiago Vernia ¹ ² ¹⁴ , Vassilis G Gorgoulis ¹¹ ¹⁵ ¹⁶ ¹⁷ , Suchira Gallage ⁸ ⁹ , Mathias Heikenwälder ⁸ ⁹ , Zoe Hall ⁵ , Andrea Alimonti ⁶ ⁷ , Iain A McNeish ¹² , Edward W Tate ³ ⁴ , Jesús Gil ¹⁸ ¹⁹

Affiliations

1. MRC Laboratory of Medical Sciences, Du Cane Road, London, UK.
2. Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
3. Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK.
4. The Francis Crick Institute, London, UK.
5. Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
6. Institute of Oncology Research, Bellinzona, Switzerland.
7. Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
8. University of Tübingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3 Research Center for Malignome, Metabolome and Microbiome, Tübingen, Germany.
9. German Cancer Research Center, Division of Chronic Inflammation and Cancer, Heidelberg, Germany.
10. Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
11. Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
12. Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
13. Centre for Molecular Cell Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.
14. Institute of Biomedicine of Valencia, CSIC and Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe-associated unit to the IBV-CSICC, Valencia, Spain.
15. Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
16. Biomedical Research Foundation, Academy of Athens, Athens, Greece.
17. Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
18. MRC Laboratory of Medical Sciences, Du Cane Road, London, UK. [email protected].
19. Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK. [email protected].

Abstract

Senescent cells drive ageing and age-related pathologies, including Cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the Glutathione Peroxidase GPX4 as a target. We show that senescent cells are primed for Ferroptosis, displaying high levels of oxidative stress and intracellular Fe²⁺, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by Ferroptosis. The combination of Anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian Cancer. Our results show that senescent cells rely on GPX4 to prevent Ferroptosis and that GPX4 inhibitors kill senescent cells.