O-GlcNAcylation regulates endometrial decidualization through dual mechanisms: PI3K-AKT axis-mediated phosphorylation...

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.

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.

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.