@article{Gil:2026,
author = {Gil, J},
journal = {Nature Cell Biology},
title = {Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability},
year = {2026}
}

Download

TY  - JOUR
AB  - 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.
AU  - Gil,J
PY  - 2026///
SN  - 1465-7392
TI  - Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability
T2  - Nature Cell Biology
ER  - 

Download