Compartment-Specific Aberrant YAP Activation Impairs Endometrial Receptivity and Decidualization in Recurrent...

The Hippo-YAP signaling pathway is crucial for tissue homeostasis, yet its specific contribution to recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) remains poorly understood. This study investigated Hippo-YAP signaling in physiological and pathological human endometrium, and its functional impact on endometrial receptivity and decidualization. We analyzed endometrial tissues from fertile controls, RIF patients, and RPL patients, complemented by mechanistic studies in Ishikawa cells and telomerase-immortalized human endometrial stromal cells (T-hESCs). In fertile controls, YAP was progressively downregulated and phosphorylated from the proliferative to the secretory and decidual phases. Conversely, RIF and RPL endometria exhibited sustained YAP activation with distinct compartment-specific patterns: YAP was upregulated in the RIF epithelium, but in the RPL stroma. Mechanistically, estradiol promoted YAP nuclear translocation and activation via estrogen receptor, whereas progesterone antagonized this effect predominantly via progesterone receptor. Public ChIP-seq data analysis supported ERα/PR occupancy at the YAP promoter-proximal regulatory region. In functional assays, YAP overexpression significantly impaired JAR spheroid attachment to endometrial epithelial cells and suppressed key genes involved in receptivity. For stromal cells, YAP overexpression disrupted in vitro decidualization, as evidenced by morphological abnormalities and the suppression of PRL and IGFBP1. Conversely, inhibition of YAP using siRNA or verteporfin promoted epithelial receptivity and stromal decidualization. Our findings reveal that progesterone-mediated downregulation of YAP is a fundamental prerequisite for endometrial receptivity and decidualization. The spatiotemporal persistence of YAP activity, dictated by impaired progesterone signaling, orchestrates compartment-specific dysfunctions that underpin the clinical divergence between RIF and RPL.