Testosterone disrupts trophoblast function and immune homeostasis via PTGER4/cAMP/RAP1 and ANXA1-FPR1 signaling in...

Polycystic ovary syndrome (PCOS) and preeclampsia (PE) are closely associated conditions, with elevated testosterone levels in PCOS significantly increasing PE risk. This study aimed to elucidate the shared molecular mechanisms linking PCOS and PE, with a particular focus on testosterone-mediated placental dysfunction and immune dysregulation.

Integrative bioinformatics analysis of transcriptome data from PCOS and PE patients identified common differentially expressed genes. Human trophoblast cells (HTR-8/SVneo) were treated with testosterone (10 μM) to model pathogenesis. RNA sequencing, RT-qPCR, histopathology, scRNA-seq, and CellChat analysis were used to explore gene regulation and cellular interactions, with functional assays validating key pathways.

We identified 418 common DEGs between PCOS and PE using bioinformatics analysis. In vitro, testosterone upregulated PTGER4 in HTR-8/SVneo cells, with PTGER4 showing stepwise increases in PCOS and PCOS-complicated PE, correlating with disease severity. Functional enrichment highlighted Ras-associated protein 1 (RAP1) and immune pathways. Mechanistically, testosterone treatment suppressed trophoblast function (migration and invasion) via PTGER4/cAMP/RAP1 axis suppression. Furthermore, PTGER4/cAMP/RAP1 signaling dysregulation reduced ANXA1 expression in trophoblasts, impaired ANXA1-FPR1-mediated EVT-macrophage communication, and promoted M1 macrophage polarization and pro-inflammatory responses, thereby contributing to the pathogenesis of PCOS-complicated PE.

This study provides significant insights into the molecular mechanisms linking PCOS and PE, emphasizing the role of hyperandrogenism in placental dysfunction and immune dysregulation.