USP5 stabilizes FoxM1 to enhance trophoblast proliferation, invasion and migration in recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) is a pregnancy-related disease with a complex etiology. Dysregulation of the migration and invasion of trophoblasts has been implicated in RSA. However, the precise mechanisms affecting trophoblast functions remain unidentified. Ubiquitin-specific protease 5 (USP5) is recognized as a critical regulator of ubiquitination, yet its role in RSA has not been fully elucidated. In this study, we observed a reduction in USP5 expression levels in the villous tissues of patients with RSA. Furthermore, USP5 knockdown significantly decreased forkhead box M1 (FoxM1) expression; reduced trophoblast proliferation, migration and invasion; and increased apoptosis, whereas overexpression of USP5 resulted in the opposite effects. Additional experiments demonstrated the significant colocalization of USP5 and FoxM1 within the nucleus. Mechanistically, USP5 was found to facilitate the deubiquitination of FoxM1, thereby stabilizing FoxM1 expression. Our findings further indicated a reduction in FoxM1 expression in the villous tissues of patients with RSA, and FoxM1 overexpression reversed the impairment of trophoblast invasion and migration caused by USP5 knockdown. Collectively, the results of this study elucidate the critical role of USP5 in regulating trophoblast function, highlighting its potential as a therapeutic target for RSA.