Uterine essential molecules in the uterus for successful implantation: analysis of an <i>in vivo</i> model

Approximately 17.5% of couples worldwide are affected by infertility. Recurrent implantation failure (RIF) affects approximately 20% of patients with infertility undergoing assisted reproductive technology (ART). Although embryonic factors have been addressed using pre-implantation genetic testing, uterine factors remain poorly understood. This review discusses our recent findings on the key molecular factors essential for uterine receptivity and embryo implantation, emphasizing the findings from genetically modified mouse models. Embryonic implantation involves three precisely regulated phases: apposition, attachment, and invasion. In this review, we focus on cyclooxygenase (COX)-mediated prostaglandin (PG) signaling and the Forkhead Box A2 (FOXA2)-LIF-STAT3 signaling axis. COX enzymes, particularly COX-2, regulate decidualization and embryo invasion via PG synthesis. FOXA2-induced leukemia inhibitory factor (LIF) expression in uterine glands is essential for initiating embryo attachment and subsequent stromal LIF expression, thereby contributing to implantation chamber formation. LIF activates epithelial STAT3 signaling and facilitates morphological transformations crucial for implantation. Further understanding of these signaling pathways may yield insights into the mechanisms of implantation, potentially guiding the development of novel therapeutic strategies for RIF.