USP1 represses ferroptosis in endometrial carcinoma cells by regulating the ubiquitination and stability of ESR1.

Endometrial carcinoma (EC) is a prevalent gynecologic malignancy. Ferroptosis, a type of programmed cell death, holds promise as a therapeutic strategy for cancer treatment. However, the specific role of ferroptosis and the underlying mechanisms in EC cells remain largely unexplored. In this study, we identified ubiquitin-specific protease 1 (USP1) as a key inhibitor of ferroptosis in EC cells. Our findings show that USP1 expression is reduced in EC cells undergoing ferroptosis but is elevated in EC tissues. Overexpressing USP1 significantly enhanced cell viability, colony formation, cell cycle progression, and migration/invasion capabilities, while strongly suppressing ferroptosis induced by the ferroptosis activator erastin. Through bioinformatic analysis and functional validation, we identified estrogen receptor 1 (ESR1) as a USP1-interacting protein involved in ferroptosis regulation. USP1 was shown to interact with ESR1, reduce its polyubiquitination, and enhance its protein stability. Rescue experiments revealed that ESR1 overexpression counteracted the pro-ferroptotic effects of USP1 depletion in erastin-treated EC cells. Finally, in vivo studies using an EC xenograft model confirmed the anti-ferroptotic and tumor-promoting role of the USP1-ESR1 axis. Together, our findings reveal a novel mechanism by which USP1 promotes EC progression through suppression of ferroptosis via ESR1 stabilization. Thus, targeting the USP1-ESR1 signaling axis may offer a new therapeutic strategy for EC.