Altered glutamine/α-ketoglutarate metabolism associates with decidualization defects in recurrent implantation...

In brief: Recurrent implantation failure (RIF) presents a significant challenge in reproductive medicine, with dysfunctional endometrial decidualization being a key underlying factor. This study identifies the glutamine/α-ketoglutarate (α-KG) metabolic axis as crucial for decidualization and demonstrates that α-KG supplementation can improve pregnancy outcomes, offering a potential therapeutic strategy for RIF. Abstract: Endometrial decidualization is a critical determinant of embryo implantation, and disruption in this process can lead to implantation failure. While various metabolic pathways regulate decidualization, the detailed metabolic characteristics and the mechanisms behind this remain unclear. Here we identified that during the process of decidualization, the concentrations of glutamine (Gln) and α-ketoglutarate (α-KG) were significantly elevated. Impaired Gln/α-KG metabolism disrupts decidualization and triggers metabolic reprogramming characterized by decreased oxidative phosphorylation and glycolysis, leading to defective trophoblast spheroid adhesion and spreading. Further analysis revealed Gln/α-KG metabolic abnormalities in the endometrial tissue of patients with recurrent implantation failure (RIF). Notably, supplementation with α-KG promotes decidualization and improves pregnancy outcomes (i.e., implantation number and pregnancy rate) in mice with impaired Gln/α-KG metabolism. Thus, our study highlights the Gln/α-KG metabolic axis as a key player in RIF, offering a scientific rationale for innovative preventive and therapeutic approaches.