IGFBP5 Restores Endometrial Receptivity and Rescues Implantation Failure in Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a metabolic disorder and a major cause of infertility, affecting approximately 5-18% of women of reproductive age worldwide. Emerging evidence suggests that intrinsic endometrial defects play a critical role in PCOS-associated infertility; however, the underlying molecular mechanisms remain poorly understood. In this study, we demonstrated that interleukin 22 (IL-22) signaling directly modulated endometrial function and that downregulation of the IL-22-STAT3 pathway contributed to impaired endometrial receptivity in PCOS. Consistently, exogenous IL-22 administration in a PCOS-like mouse model restored STAT3 phosphorylation and effectively alleviated implantation failure by enhancing endometrial receptivity. Mechanistically, we identified insulin-like growth factor-binding protein 5 (IGFBP5) as a direct downstream target of STAT3 in endometrial organoids derived from patients with PCOS. Knockdown of IGFBP5 in the uteri of PCOS-like mice abolished the beneficial effects of IL-22, whereas IGFBP5 supplementation restored endometrial receptivity and rescued implantation. Collectively, we showed that the suppression of the IL-22-STAT3-IGFBP5 axis is a key contributor to impaired endometrial receptivity in PCOS, providing a potential therapeutic target for improving pregnancy outcomes via IGFBP5 supplementation.

Keywords: IGFBP5; IL‐22‐STAT3 signaling pathway; endometrial organoids; endometrial receptivity; polycystic ovary syndrome.