Decreased OGT Attenuates Endometrial Decidualization and Embryo Implantation by Affecting HIF‐1α Stability

Hypoxia-inducible factor 1-alpha (HIF-1α) is essential for glycolysis regulation. Its expression in the endometrium is significantly reduced in recurrent implantation failure (RIF), indicating that lower levels of HIF-1α may contribute to embryo implantation failure. O-GlcNAcylation is a dynamic posttranslational modification mediated by O-GlcNAc transferase (OGT), known to regulate HIF-1α in cancer cells. However, it remains unclear whether OGT affects glycolytic processes in uterine endometrial stromal cells (ESCs) and its potential role in embryo implantation. This study utilized In Vitro and In Vivo experiments to investigate the role of OGT in decidualization and embryo implantation, along with its underlying mechanisms. Our findings show that OGT expression is significantly reduced in the endometrium of patients with RIF. Additionally, OGT knockdown led to failed embryo implantation in mice. Further analysis revealed that OGT promotes decidualization by stabilizing HIF-1α, which enhances glycolytic activity. Inhibiting OGT resulted in insufficient decidualization among human ESCs. Moreover, our results indicate that OGT partially regulates CCL2 secretion by maintaining HIF-1α levels within human ESCs, which is essential for successful embryo implantation. Based on these findings, we propose that OGT represents a novel and promising therapeutic target for both the diagnosis and treatment of RIF.