Inhibition of IGFBP4 in Granulosa Cells Improves Reproductive Performance and Maintains Fertility With Age via YAP Signaling

ABSTRACT Ovarian aging is a critical factor influencing reproductive capacity and overall health. Granulosa cells (GCs) play essential roles in folliculogenesis; however, the mechanisms by which GC dysfunction contributes to ovarian aging remain incompletely understood. In this study, we identified insulin‐like growth factor binding protein 4 (IGFBP4) as a negative regulator of ovarian function that is upregulated in GCs from aged cynomolgus monkey ovaries. Using an Igfbp4 ‐HA tagged mouse model, we found that IGFBP4 expression in GCs increased during follicle development and was further elevated in aged mice. RNA‐seq analysis of Igfbp4 ‐deficient GCs revealed activation of the YAP pathway, which supports follicular development. Mechanistically, IGFBP4 reduced YAP nuclear localization in GCs, thereby restraining downstream YAP target gene expression and GC proliferation. In Amhr2‐Cre; Igfbp4 ^fl/fl mice, GC‐specific deletion of Igfbp4 enhanced folliculogenesis, increased litter size and preserved reproductive performance with age. Elevated IGFBP4 levels were also detected in GCs from aging women and patients with premature ovarian insufficiency (POI). Furthermore, higher concentrations of IGFBP4 were observed in the follicular fluid of POI patients, supporting its potential as a biomarker of ovarian dysfunction. These findings establish IGFBP4 as a GC‐derived suppressor of ovarian function and a potential target for preserving ovarian function during aging.