Ypel5 preserves female fertility by regulating folliculogenesis and oocyte maturation.

Maintaining the primordial follicle pool and precisely regulating folliculogenesis are critical for female fertility. Despite advances in understanding ovarian development, the molecular mechanisms safeguarding follicle survival and oocyte maturation remain incompletely defined. Here, we identify YPEL5 as an essential regulator of folliculogenesis and oocyte development. Using an oocyte-specific conditional knockout (cKO) mouse model, we demonstrate that Ypel5 deletion causes complete female infertility, characterized by accelerated depletion of the primordial follicle pool, defective antral follicle formation, and impaired oocyte maturation. Loss of Ypel5 results in increased DNA damage, disrupted mitochondrial homeostasis, elevated oxidative stress, and ultimately triggers apoptotic depletion of primordial follicle oocytes. Moreover, Ypel5-deficient oocytes exhibit severe abnormalities in spindle organization and mitochondrial distribution, culminating in defective oocyte maturation. Collectively, these findings establish YPEL5 as a critical regulator of follicle development and oocyte maturation, and provide mechanistic insights into the molecular basis of female infertility.