Researchers Identify GPX4 Inhibitors That Target Senescent Cells in Cancer Models

Scientists have discovered a class of compounds that target and eliminate senescent cells, often referred to in research as persistent cells that contribute to aging and disease, including cancer. The research involved screening a library of 10,480 electrophilic compounds to identify those with senolytic activity, meaning they selectively kill senescent cells.

Among the hits, 38 compounds demonstrated senolytic effects, including a subset of chloroacetamides that target the enzyme glutathione peroxidase 4 (GPX4). The screen used IMR90 human lung fibroblasts induced into senescence via an ER:RAS fusion protein, as well as SK-MEL-103 melanoma cells induced by etoposide or tozasertib.

Four specific chloroacetamides, labeled SCLA1 through SCLA4, showed selective killing of senescent cells in dose-response tests, with EC50 values lower in senescent cells compared to non-senescent ones.

Senescent cells exhibit high oxidative stress and intracellular iron levels, priming them for ferroptosis, a form of cell death. These cells upregulate GPX4 to prevent lipid oxidation, making GPX4 inhibition effective in triggering ferroptosis specifically in senescent cells.

In preclinical models, combining anticancer therapies with GPX4 inhibitors eliminated senescent tumor cells in melanoma, prostate, and ovarian cancer.

Senescent cells arise as a protective response to damage or cancer but can persist and contribute to pathologies when they accumulate. Existing senolytics include compounds like quercetin, fisetin, BCL2 inhibitors such as ABT-263 and ABT-737, and others targeting different cellular vulnerabilities.