IGFBP2 Protein Loss Drives Uterine Cell Aging Behind Thin Endometrium

Thin endometrium (TE) is a clinically significant but poorly understood condition associated with reduced implantation success and adverse pregnancy outcomes. Despite its impact on fertility, the molecular mechanisms driving endometrial thinning have remained largely unclear — until now.

Researchers at Nanjing Drum Tower Hospital analyzed single-cell RNA sequencing datasets from patients with thin endometrium and identified a consistent downregulation of insulin-like growth factor binding protein 2 (IGFBP2) in endometrial epithelial cells. This reduction was associated with increased cellular senescence, a state of irreversible cell cycle arrest that impairs tissue regeneration and function.

In laboratory experiments using both primary human endometrial epithelial cells and the Ishikawa endometrial cell line, the team demonstrated that introducing recombinant IGFBP2 protein could effectively reverse hydrogen peroxide-induced cellular senescence. Mechanistically, IGFBP2 silencing via siRNA led to elevated p21 (CDKN1A) — a key senescence marker — through PTEN-mediated suppression of the PI3K/AKT signaling pathway. Notably, IGFBP2 supplementation matched or outperformed Dasatinib, a well-known senolytic drug, in several senescence-reduction metrics.

In a mouse model of thin endometrium created by endometrial curettage combined with hydrogen peroxide instillation, administration of either IGFBP2 protein or Dasatinib successfully restored endometrial thickness by inhibiting senescence pathways. These findings position IGFBP2 as a central mediator of endometrial cell aging and tissue dysfunction in TE.

While results are promising, the study is limited by its reliance on cell lines, a chemically induced mouse model, and the absence of clinical trial data. Translation to human fertility treatments will require further validation in larger preclinical and clinical settings.