Egr1-mediated transcription of LRRC1 impairs endometrial receptivity in recurrent implantation failure by disrupting PP1A–YAP interaction

A receptive endometrial epithelium is prerequisite for successful embryo implantation. Impaired endometrial receptivity has been associated with recurrent implantation failure (RIF), a major challenge in assisted reproductive technology with limited treatment options. However, the underlying molecular mechanisms remain inadequately understood. This study aims to investigate the role of leucine-rich repeat-containing protein 1 (LRRC1) in modulating endometrial receptivity of RIF. Endometrial tissues were collected from 15 RIF patients and 15 control women in the mid-secretory phase, as well as 28 individuals across the normal menstrual cycle. The expression of LRRC1 was assessed by qRT-PCR, Western blotting, and immunohistochemistry. Three endometrial epithelial cell lines (HEC-1 A, Ishikawa, and RL95-2) were used for siRNA or plasmid transfection and subjected to functional analyses via CCK-8, colony formation, wound healing, transwell, and JAR trophoblast adhesion assays. Protein interaction and transcriptional regulation were explored using co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays. Intrauterine injection of LRRC1-overexpressing plasmids in mice was performed to evaluate implantation outcomes. LRRC1 was significantly upregulated in the endometrial epithelium of RIF patients during the implantation window. Across the menstrual cycle, its expression peaked in the proliferative phase and progressively declined throughout the secretory phase. Functionally, LRRC1 inhibited endometrial epithelial cell proliferation, migration, invasion and adhesion to trophoblast in vitro, and reduced the number of embryo implantation sites in vivo. Mechanistically, LRRC1 interacted with protein phosphatase 1 A (PP1A) and reduced PP1A binding to yes-associated protein (YAP), thereby attenuating YAP dephosphorylation and promoting its cytoplasmic retention and inactivation. Importantly, a phosphorylation-defective YAP mutant (S127A) partially rescued the functional deficits induced by LRRC1 overexpression. Upstream, early growth response 1 (Egr1) was identified as a transcriptional suppressor of LRRC1, and its expression was also significantly decreased in RIF endometrium. Our work uncovers a novel Egr1-LRRC1-PP1A-YAP signaling axis in the regulation of endometrial receptivity. The findings expand the understanding into the pathogenesis of RIF and may offer potential therapeutic targets for affected women.