Transcription Factor XBP1s Impairs Endometrial Receptivity by Promoting ENO1-Mediated Glycolysis and Lactate Production

Successful embryo implantation necessitates formation of a complex and tight connection between a well-developed embryo and highly receptive endometrium. Type I interferon IFN-τ is a pregnancy recognition signal in ruminants that promotes the establishment of endometrial receptivity. However, the mechanisms that underpin this process largely remain unknown. Previous CUT&Tag assays revealed that XBP1s preferentially targets genes in the glycolytic pathway. In this study, we found that IFN-τ significantly inhibited glycolysis and lactate production during peri-implantation. In addition, overexpression of XBP1s reversed the inhibition of glycolysis by IFN-τ and promoted expression of glycolysis rate-limiting enzymes (HK1, PFK-1, and PKM1) and lactate production. Dual-luciferase reporter and electrophoretic mobility shift assays demonstrated that XBP1s directly binds to the promoter of the ninth step gene of glycolysis, ENO1. Moreover, ENO1 and XBP1s exhibited congruent expression patterns, and both factors also reversed IFN-τ-induced endometrial receptivity and inhibition of glycolysis. In contrast, knockdown of ENO1 enhanced the effects of IFN-τ. Interestingly, lactate also inhibited the establishment of endometrial receptivity and PGES expression. In conclusion, our data suggest that XBP1s negatively regulates endometrial function through the transcriptional regulation of ENO1-promoted lactate production. This study provides key insights into the mechanisms by which XBP1s acts in female reproductive development.