Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability
File(s)
Published version
Author(s)
Type
Journal Article
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. Amongst 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 oxidised 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.
therapeutic appeal. Here, we report a senolytic screen of a library of 10,480 electrophilic compounds. Amongst 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 oxidised 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.
Date Issued
2025-05-01
Date Acceptance
2026-02-26
Citation
Nature Cell Biology, 2025, 28 (5), pp.915-929
ISSN
1465-7392
Publisher
Nature Research
Start Page
915
End Page
929
Journal / Book Title
Nature Cell Biology
Volume
28
Issue
5
Copyright Statement
© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41556-026-01921-z
Publication Status
Published
Date Publish Online
2026-04-24