Inhibition of IGFBP4 in granulosa cells extends female fertility age via activation of YAP signaling

Ovarian aging is a critical factor in determining reproductive capacity and overall health. Granulosa cells (GCs) play an essential role in folliculogenesis. However, the mechanisms through which GCs influence ovarian aging remain poorly understood. This study identifies insulin-like growth factor binding protein 4 (IGFBP4) as a negative regulator of female fertility. Elevated expression of IGFBP4 is observed in the GCs of aged ovaries in cynomolgus monkey. Using IGFBP4-HA tagged mice, we observed increased levels of IGFBP4 in aged GCs and during follicular atresia in mice. Our findings indicate that IGFBP4 inhibits GCs proliferation by attenuating YAP signaling. In Amhr2-Cre; Igfbp4fl/fl mice, GC-specific deletion of Igfbp4 leads to enhanced folliculogenesis and increased litter sizes, notably extending the reproductive lifespan of these mice. Elevated levels of IGFBP4 were also detected in GCs from aging individuals and patients with premature ovarian insufficiency (POI). Furthermore, higher concentrations of IGFBP4 were found in the follicular fluid of POI patients, suggesting its potential as a clinical diagnostic marker. These findings underscore the possibility of extending female fertility through the inhibition of IGFBP4 in GCs, proposing a novel strategy for enhancing women's reproductive health.