The roles of the STAT3 signaling pathway in the establishment of endometrial receptivity and decidualization

Abstract The establishment of endometrial receptivity is a fundamental prerequisite for successful embryo implantation and the maintenance of pregnancy. Decidualization, a critical process in the maturation of endometrial receptivity, is intimately linked to implantation success. The precise molecular regulation of both processes is essential for normal pregnancy outcomes. Within the endometrium, the activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) exhibits strict temporal and spatial specificity. Its phosphorylation levels peak during the mid-secretory phase, aligning perfectly with the window of implantation, thereby establishing STAT3 as a primary indicator of endometrial receptivity. Activated by crucial cytokines—including leukemia inhibitory factor (LIF), interleukin (IL)-11, and epidermal growth factor (EGF)—STAT3 operates through the Janus kinase (JAK)/STAT signaling pathway. It regulates the functional maturation, adhesive capacity, and polarity remodeling of endometrial epithelial cells, creating an optimal environment for blastocyst attachment. Concurrently, STAT3 acts as a central regulator of decidualization by directly driving the proliferation and differentiation of endometrial stromal cells (ESCs) while maintaining the stability of the decidual microenvironment. Furthermore, STAT3 modulates the local immune milieu by orchestrating immune cell polarization and cytokine networks, providing essential immunological support. Conversely, dysregulation of the STAT3 signaling pathway leads to impaired endometrial receptivity and defective decidualization, contributing to adverse reproductive outcomes such as implantation failure and miscarriage. This review comprehensively highlights the pivotal regulatory functions of the STAT3 pathway in endometrial receptivity and decidualization, establishing a robust theoretical foundation for future basic research and targeted clinical strategies.