IDO1-Kyn-AhR Axis Mediates Glutamine/α-Ketoglutarate-Dependent Decidualization in Recurrent Implantation Failure

One of the principal pathogens in recurrent implantation failure (RIF) is poor decidualization. Although various factors have been identified as involved in regulating decidualization, much remains unknown. Studies have shown that the decidualization process is accompanied by active glutamine/α-ketoglutarate (α-KG) metabolism, but the specific mechanisms warrant further investigation. Here, through RNA-Seq, we have discovered that α-KG may regulate decidualization via indoleamine 2,3-dioxygenase 1 (IDO1), one of the key enzymes involved in the conversion of tryptophan to kynurenine. Mechanistically, this process relies on the demethylation of H3K27me3 in the IDO1 promoter region, thereby regulating the IDO1-Kyn-Aryl hydrocarbon receptor (AhR) pathway. At the same time, RIF patients exhibit downregulated glutamine/α-KG/IDO1 metabolism in the endometrium compared with fertile women. In mouse models with disrupted glutamine/α- KG metabolism, supplementation with α-ketoglutarate or tryptophan promotes decidualization and enhances pregnancy rates. Consequently, this study underscores the pivotal role of the glutamine/α- KG /IDO1 metabolic axis in the prevention and treatment of implantation failure.