USP26-mediated stabilization of RAD51 promotes endometrial cancer progression and limits ferroptosis

Background Ferroptosis is increasingly implicated in endometrial cancer, but the role of the homologous recombination protein RAD51 in ferroptotic stress and its post-translational regulation remain unclear. Methods RAD51 expression was assessed in GEO datasets, UCEC tissues, and endometrial cancer cell lines. RAD51 loss-of-function was evaluated using proliferation, cell-death, Transwell, ferroptosis-related, and xenograft assays. IP–MS, co-immunoprecipitation, cycloheximide chase, proteasome inhibition, ubiquitination assays, USP26-C304S, and RAD51 rescue experiments were used to define USP26-dependent RAD51 regulation. Results RAD51 was upregulated in endometrial cancer and its depletion reduced proliferation and xenograft growth, lowered Transwell migration/invasion readouts, and increased ferroptosis-associated changes. USP26 associated with RAD51, reduced its ubiquitination, and stabilized RAD51 in a catalytic activity-dependent manner. RAD51 re-expression partially rescued the effects of USP26 depletion. Conclusions The USP26–RAD51 axis supports endometrial cancer progression and limits ferroptosis-associated stress, identifying RAD51 protein stability as a potential mechanistic vulnerability.