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Updated: May 23, 2026
SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability
Mariantonietta D'Ambrosio1,2, Matthew E H White1,3,4, Efthymios S Gavriil3
1MRC Laboratory of Medical Sciences, Du Cane Road, London, UK.
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.
Insights
Senescent cells, linked to aging and cancer, can be targeted by senolytics. New research identifies GPX4 inhibitors as effective senolytics that kill senescent cells via ferroptosis.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Senescent cells contribute to aging and age-related diseases, including cancer.
- Senolytics offer therapeutic potential by selectively eliminating senescent cells.
Purpose of the Study:
- To identify novel senolytic compounds targeting senescent cells.
- To elucidate the mechanism by which senolytics eliminate senescent cells.
Main Methods:
- Screening of 10,480 electrophilic compounds to identify senolytics.
- Activity-based protein profiling and functional assays to identify drug targets.
- Investigating the role of glutathione peroxidase 4 (GPX4) in senescent cell survival.
Main Results:
- A subset of chloroacetamides demonstrated broad senolytic activity.
- Glutathione peroxidase 4 (GPX4) was identified as a key target.
- Senescent cells, primed for ferroptosis, upregulate GPX4 to prevent lipid peroxidation.
- GPX4 inhibitors selectively induce ferroptosis in senescent cells, including in cancer models.
Conclusions:
- Senescent cells depend on GPX4 to evade ferroptosis.
- GPX4 inhibitors represent a promising therapeutic strategy for eliminating senescent cells.
- Combining GPX4 inhibitors with anticancer therapies can eliminate senescent tumor cells.
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