PTN/IGF-2 signaling modulates endometrial decidualization and immune cell trafficking to facilitate pregnancy maintenance

Background Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) are major causes of pathological early pregnancy, yet their mechanisms remain poorly understood. This study aimed to identify shared molecular mediators and their roles in endometrial dysfunction and immune regulation. Methods Gene expression datasets for RIF and RPL were analyzed for differentially expressed genes (DEGs), functional enrichment, and protein–protein interaction (PPI) networks. Key regulators were identified using CytoHubba and Random Forest, and receiver operating characteristic (ROC) analysis evaluated their diagnostic performance. Endometrial stromal cells (ESCs) from RIF or RPL patients were used for in vitro functional assays, and in vivo murine models with in situ uterine PTN knockdown and IGF-2 rescue were established to assess pregnancy outcomes. RT-qPCR, immunoblotting, immunofluorescence, and flow cytometry were performed to assess decidualization markers and immune cell compositions. Results PPI network and machine learning analysis identified PTN as a central hub gene shared by RIF and RPL. ROC curves showed that PTN had the highest diagnostic value among all candidate genes. Immunofluorescence confirmed that PTN is mainly expressed in ESCs and downregulated in RIF and RPL patients. In vitro , PTN promoted decidualization markers (IGFBP1, PRL, IGF-2, WNT4, and LIF) and modulated immune cell composition via IGF-2. In vivo , uterine PTN knockdown impaired implantation, reduced embryo numbers, and increased embryo resorption rates, while IGF-2 supplementation partially rescued these defects. These results indicate that PTN regulates ESC decidualization and endometrial immune tolerance and serves as a highly predictive biomarker for pathological pregnancies in RIF and RPL. Discussion The PTN/IGF-2 axis promotes ESC decidualization and a tolerogenic immune microenvironment, supporting endometrial receptivity. Dysregulation of this pathway may underlie pathological pregnancies (including RIF and RPL), highlighting PTN as a potential therapeutic target for early pregnancy loss.