LRRC1 protein linked to implantation failure in new study

Researchers have identified a molecular pathway that appears to impair endometrial receptivity in women with recurrent implantation failure, a major challenge in assisted reproductive technology with limited treatment options. The study, published in Biology Direct on 27 October 2026, focuses on leucine-rich repeat-containing protein 1 (LRRC1), a protein the authors found to be significantly upregulated in the endometrial epithelium of patients with recurrent implantation failure during the implantation window.

The research team, led by Lingling Huang, Liping Zou and Bin Yang with Jialyu Huang as senior author, examined endometrial tissues collected from 15 recurrent implantation failure patients and 15 control women in the mid-secretory phase, as well as 28 individuals sampled across the normal menstrual cycle. Using qRT-PCR, Western blotting and immunohistochemistry, they assessed LRRC1 expression in these samples.

Across the menstrual cycle, LRRC1 expression peaked in the proliferative phase and progressively declined throughout the secretory phase. This pattern is notable because the mid-secretory phase corresponds to the implantation window, when the endometrial epithelium must become receptive for successful embryo implantation. Elevated LRRC1 in recurrent implantation failure patients at this precise stage suggested to the authors that the protein may interfere with the receptive state.

To test functional effects, the team used three endometrial epithelial cell lines, HEC-1A, Ishikawa and RL95-2, in which they manipulated LRRC1 levels through siRNA or plasmid transfection. Functional analyses included CCK-8 proliferation assays, colony formation, wound healing, transwell migration and invasion assays, and JAR trophoblast adhesion assays. Across these in vitro experiments, LRRC1 inhibited endometrial epithelial cell proliferation, migration, invasion and adhesion to trophoblast cells, all processes relevant to establishing a receptive endometrium.

The mechanistic core of the study concerns an interaction between LRRC1 and protein phosphatase 1 A (PP1A). Using co-immunoprecipitation, the researchers found that LRRC1 interacts with PP1A and reduces PP1A binding to yes-associated protein (YAP), a transcriptional regulator controlled in part by its phosphorylation status. With less PP1A available to bind YAP, YAP dephosphorylation is attenuated, promoting its retention in the cytoplasm and its inactivation.

Supporting this mechanism, a phosphorylation-defective YAP mutant, S127A, partially rescued the functional deficits induced by LRRC1 overexpression in the cell models. This rescue experiment links the LRRC1–PP1A interaction to YAP phosphorylation status and to the observed cellular defects, although the rescue was partial rather than complete in the reported in vitro findings.

Upstream of LRRC1, the team identified early growth response 1 (Egr1) as a transcriptional suppressor of LRRC1. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to explore this transcriptional regulation. Notably, Egr1 expression was also significantly decreased in the endometrium of recurrent implantation failure patients, consistent with a model in which reduced Egr1 permits elevated LRRC1 expression.

To evaluate effects in a living system, the researchers performed intrauterine injection of LRRC1-overexpressing plasmids in mice. This in vivo experiment showed that elevated LRRC1 reduced the number of embryo implantation sites, providing animal-model evidence that the protein can affect implantation outcomes, though the mouse model does not directly replicate the human clinical condition.

The authors conclude that their work uncovers a novel Egr1–LRRC1–PP1A–YAP signaling axis in the regulation of endometrial receptivity. They state that the findings expand understanding of the pathogenesis of recurrent implantation failure and may offer potential therapeutic targets for affected women. As the study is an early-release, peer-reviewed accepted article that remains subject to further edits before the final Version of Record, the reported associations and mechanisms will be evaluated further as the work enters wider scientific discussion. The findings are based on a relatively small human cohort of 15 patients and 15 controls, and the functional work relies on cell lines and a mouse model, so translation to clinical practice remains a question for future research.

Subject of Research: The role of LRRC1 and the Egr1–LRRC1–PP1A–YAP signaling axis in impaired endometrial receptivity in recurrent implantation failure.

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

Article References: Huang, L., Zou, L., Yang, B., Jiang, R., Chen, Z., Xiong, C., Deng, Y., Li, Z., Zhao, Y., Lin, J., & Huang, J. (2026). Egr1-mediated transcription of LRRC1 impairs endometrial receptivity in recurrent implantation failure by disrupting PP1A–YAP interaction. Biology Direct. https://doi.org/10.1186/s13062-026-01037-2

Image Credits: AI Generated

DOI: 10.1186/s13062-026-01037-2

Keywords: recurrent implantation failure, endometrial receptivity, LRRC1, Egr1, PP1A, YAP, embryo implantation, assisted reproductive technology, endometrial epithelium, molecular mechanism, Egr1-mediated, transcription