Inhibition of SLC38A2 and loss of its N-glycosylation impair decidualization by promoting autophagy and apoptosis.

Decidualization plays a crucial role in embryo implantation and successful pregnancy. Dysregulation and dysfunction of decidualization caused by any factor may lead to a variety of pregnancy related disorders. However, many underlying molecular pathways regulating decidualization remain unknown, especially the impact of glycosylation. Protein glycosylation is vital for maternal fetal crosstalk, and its aberrance may result in adverse pregnancy outcomes. This study focused on SLC38A2, a member of the solute carrier family (neutral amino acid transporter), to investigate its function in endometrial decidualization and the effect of its N-glycosylation modification. Our results demonstrated that SLC38A2 was highly expressed in mouse endometrial stromal cells during the peri implantation period and in in vitro decidualized endometrial stromal cells (ESCs), and inhibition of SLC38A2 impeded the decidualization process. N-glycosylation of SLC38A2 was essential for its function by affecting protein stability and membrane localization, as well as its glutamine transport activity. Mechanistically, downregulation of SLC38A2 or loss of its N-glycosylation suppressed the mTOR pathway and promoted autophagy and apoptosis in decidualized ESCs. These findings suggest that SLC38A2 and its glycosylation modification may serve as potential therapeutic targets for decidual abnormalities and implantation failure, providing novel insights into how amino acid metabolic dysregulation contributes to embryo implantation failure caused by decidualization defects.