BACKGROUND: Endometrial cancer (EC) is a significant and serious gynecological cancer, constituting a considerable risk to women's health. The desumoylation of SUMO specific peptidase 5 (SENP5) is intricately linked with various cancers. Nonetheless, the function of SENP5 in EC and its regulation of EC progression through the related mechanism of desumoylation modification remain elusive. METHODS: Five samples of EC tumor tissues, along with para-cancerous tissues, were obtained. The expression of SENP5 in EC was assessed using reverse transcription-polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), and Western blot. HEC-1-B cells were treated with liposomes to interfere SENP5 and/or β-catenin expression. The methodologies employed to assess the impact of SENP5 on the proliferation of EC cells via β-catenin included RT-qPCR, Western blot, CCK8, EDU, and C11-BODIPY methods. Western blot, co-immunoprecipitation (CO-IP), and SUMOylation analysis were conducted to investigate the desumoylation modification of β-catenin by SENP5. RESULTS: SENP5 exhibited elevated expression levels in EC cancer tissues and was correlated with a negative prognosis for patients diagnosed with EC. The suppression of SENP5 inhibited the expression of β-catenin and GPX4, activated ferroptosis, and inhibited HEC-1-B -cell proliferation. Knockdown of β-catenin counteracted the impact of SENP5 overexpression on ferroptosis and HEC-1-B proliferation. In addition, SENP5 stabilized β-catenin level in HEC-1-B cells through desumoylation modification of the β-catenin protein. CONCLUSIONS: SENP5 promotes GPX4-mediated ferroptosis resistance, thereby enhancing the proliferation of EC cells by regulating β-catenin desumoylation, this finding indicates that SENP5 may serve as a promising target for therapeutic interventions in the treatment of EC.