Endometrial cancer(EC) is the most common tumors in women, with the rate of incidence and mortality has been greatly increased recently. With the wide application of targeted therapy in clinic, exploring new targets has been the most critical link in the accurate treatment of endometrial carcinoma. More and more studies have found that the E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) plays an important role in the development of EC. In this review, we analysed recent research articles in this field and focused on the current research status of EC and ubiquitin-proteasome system(UPS) , the structure and function of SPOP, factors influencing and regulating SPOP and the mutations and substrates of SPOP in EC. Moreover, we summarized the molecular role of SPOP on repressing EC mostly in three key signal pathways: estrogen receptor-α(ERα) -mediated signaling pathway, bromodomain and extraterminal protein(BET) pathway and zinc finger and BTB domain-containing protein 3(ZBTB3) pathway. We look forward to SPOP as the new molecular targeted therapy for EC.