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We report the discovery of a new way to selectively eliminate senescent cells by targeting their dependence on the antioxidant enzyme GPX4.

In , researchers from the Gil and Tate groups used a library of more than 10,000 electrophilic compounds to identify molecules that selectively kill senescent cells while sparing healthy cells. This screen uncovered a new class of senolytic chloroacetamides, and activity-based protein profiling revealed that these compounds act by targeting glutathione peroxidase 4 (GPX4), a key enzyme that protects cells from lipid oxidation.

The team showed that senescent cells exist in a state of heightened oxidative stress and are unusually sensitive to ferroptosis, a form of iron-dependent cell death. Although these cells are primed for ferroptosis, they survive by increasing GPX4 activity to prevent toxic lipid damage. Inhibiting GPX4 removed this protection and triggered selective death of senescent cells across several disease-relevant models.

Importantly, combining GPX4 inhibitors with existing anticancer treatments helped eliminate persistent senescent tumour cells in melanoma, prostate and ovarian cancer models, suggesting a promising new “one-two punch” therapeutic strategy to improve cancer treatment and reduce harmful long-term effects of therapy.

Congratulations to Dr Matthew White, Dr. Efthymios S. Gavriil and all collaborators involved in this work! This research was supported by funding from CRUK, EPSRC, MRC, Agencia Estatal de Investigación, the Nicholas and Sofula Kotopoulos Trust, the Ninewells Cancer Campaign and the Hellenic Foundation for Research and Innovation.