Multi‐Omics Data Reveal Estrogen‐Driven Dysregulation and Stromal‐Epithelial Signaling Alterations in Endometrial Polyps

ABSTRACT

Endometrial polyps (EPs) are common uterine lesions associated with abnormal uterine bleeding and infertility, yet their pathogenesis remains poorly defined. Here, we performed single‐cell RNA sequencing of normal endometrium, para‐polyp, and polyp tissues, identifying distinct cellular compositions and transcriptional programs. EPs showed enhanced estrogen signaling and increased epithelial proliferation, accompanied by decreased expression of cytokines and reduced T cell cytotoxicity. Notably, we observed epithelial subpopulations with elevated copy number variations and transcription factors associated with hyperplasia. Cell–cell communication analyzes revealed aberrant stromal‐epithelial crosstalk, characterized by upregulated WNT, IGF, and VEGF signaling originating from stromal cells. Spatial transcriptomic analyzes further demonstrated enhanced WNT signaling between stromal and epithelial compartments in endometrial cancer. In vitro glandular organoid models showed that epithelial transcriptional alterations contribute to polyp formation. These findings highlight a critical role of stromal‐epithelial interactions in EP development and suggest potential therapeutic targets.