O-GlcNAcylation regulates endometrial decidualization through dual mechanisms: PI3K-AKT axis-mediated phosphorylation and direct modification of FOXO1.

BACKGROUND: Steroid hormone-driven endometrial decidualization involves the differentiation of endometrial stromal cells into decidual cells, which form the decidua for blastocyst implantation. This process is a prerequisite for successful embryo implantation. O-GlcNAcylation is a nutrient-sensitive post-translational modification. Our prior work demonstrated that O-GlcNAcylation promotes embryo recognition by enhancing endometrial epithelial cell proliferation, migration and invasion, thereby facilitating embryo implantation. However, its regulatory role in endometrial stromal cell decidualization remains unknown.

RESULTS: In this study, we found that O-GlcNAcylation was upregulated during mouse embryo implantation and in vitro decidualization, and its downregulation impaired both embryo implantation efficiency and decidualization. Transcriptome sequencing revealed that the PI3K-AKT pathway was significantly enriched upon OGT inhibition. Mechanistically, O-GlcNAcylation likely promotes decidualization by attenuating PI3K-AKT signaling to reduce phosphorylation of the key decidualization transcription factor FOXO1, while simultaneously increasing direct O-GlcNAcylation of FOXO1, thereby enhancing its stability and nuclear retention to promote decidualization.

CONCLUSIONS: This study elucidates how O-GlcNAcylation orchestrates decidualization through FOXO1 regulation, providing important insights into the role of O-GlcNAcylation signaling in normal pregnancy and its dysregulation in decidualization-related disorders.