Disruption of the Wnt/β-Catenin and PI3K-AKT-mTOR Crosstalk in Endometrial Stromal Cells: A Case Report of Impaired Decidualization Leading to Recurrent Implantation Failure and Potential Pathway-Specific Therapeutic Interventions

Abstract

A 34-year-old woman with a long-standing history of recurrent implantation failure (RIF) and unexplained infertility presented for further evaluation. Molecular analysis revealed a significant disruption in the crosstalk between the Wnt/β-catenin and PI3K-AKT-mTOR signaling pathways, both essential for regulating endometrial receptivity and successful embryo implantation. Immunohistochemical testing showed a marked reduction in β-catenin nuclear translocation and a 65% decrease in AKT phosphorylation, leading to impaired cellular processes such as proliferation and differentiation. This disruption contributed to incomplete decidualization of the endometrium, which played a central role in her repeated implantation failures. Conventional fertility treatments, including hormone therapy and in vitro fertilization (IVF), were ineffective. Consequently, we explored targeted molecular therapies aimed at restoring functionality within these signaling pathways to enhance endometrial receptivity. This case underscores the critical role of the Wnt/β-catenin and PI3K-AKT-mTOR pathways in endometrial function and highlights the potential for novel therapeutic strategies in treating RIF by addressing specific molecular defects.

Keywords: Decidualization; Endometrial receptivity; Implantation failure; PI3K-AKT-mTO; Wnt/β-catenin.

Fig. 1

The significant reduction in nuclear β-catenin localization (30% in the patient vs. 85% in the healthy control), alongside increased cytoplasmic retention in the patient (70% vs. 15%). The patient also exhibits a marked reduction in AKT phosphorylation (35% vs. 100%) and mTOR phosphorylation (50% vs. 100%), impairing downstream signaling crucial for endometrial receptivity. Additionally, the patient shows a 45% decrease in prolactin and IGFBP-1 expression

Fig. 2

The reduction in AKT and mTOR phosphorylation disrupts essential cellular processes like cell proliferation, survival, and metabolic regulation in the endometrial stromal cells. This affects their ability to undergo decidualization, where these cells transform and prepare the endometrium for embryo implantation. Without proper proliferation and differentiation, the endometrium becomes less receptive, explaining why the patient experiences recurrent implantation failure despite good-quality embryos

Fig. 3

Wnt/β-catenin and PI3K-AKT-mTOR work together to support decidualization, an essential process in preparing the endometrium for embryo implantation. The Wnt pathway activates β-catenin, which drives TCF/LEF activity to regulate the genes needed for endometrial cell transformation. At the same time, the PI3K-AKT-mTOR pathway promotes AKT phosphorylation, leading to mTOR activation, which supports cell growth and the production of key molecules like prolactin and IGFBP-1. Both pathways converge to ensure that the endometrial cells are properly prepared for implantation. If either pathway is disrupted, as in this patient, the endometrium may not become receptive, leading to implantation failure

Fig. 4

Ki-67 dropped by 40%, integrin αvβ3 by 35%, and LIF by 30%. This points to, slower cell growth, difficulty in the embryo attaching to the uterine lining, and problems with the implantation process itself. Together, these reductions help explain why the patient has been experiencing implantation failure