Altered Glutamine/α-Ketoglutarate Metabolism Associates with Decidualization Defects in Recurrent Implantation Failure and is Ameliorated by α-Ketoglutarate Supplementation in Mice.

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 decidualisation, the concentrations of glutamine and α-ketoglutarate (α-KG) were significantly elevated. Impaired glutamine/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 glutamine/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 glutamine/α-KG metabolism. Thus, our study highlights the glutamine/α-KG metabolic axis as a key player in RIF, offering a scientific rationale for innovative preventive and therapeutic approaches.