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

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

MRC Laboratory of Medical Sciences, Du Cane Road, London, UK. · pubmed

Paper

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 Fe

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper identifies GPX4-dependent ferroptosis as a vulnerability in senescent cells, suggesting a potential therapeutic approach to target the root causes of aging. The research focuses on senolytics, which aim to selectively eliminate senescent cells, thereby addressing a key aspect of aging and age-related diseases.

Author of this paper? Send a correction.