Cellular prion protein (PrP^c) regulates ovarian reserve maintenance through anti‑Müllerian hormone (AMH)‑dependent mechanisms. The present study explored the role of PrP^c in the ovarian function of mice using complementary in vitro and in vivo models. First, prion protein gene (PRNP) knockdown or overexpression was carried out in mouse ovarian granulosa cells. In vitro analyses conducted using flow cytometry and ELISA revealed that the depletion of PrP^c specifically hindered the secretion of AMH compared with control groups, while the levels of progesterone (P4) and estradiol (E2) remained unchanged across all experimental groups. Importantly, the reduction in AMH levels was reversed upon re‑expression of PrP^c. Additionally, neither the distribution of the cell cycle nor the rates of apoptosis were affected by the manipulation of PrP^c. Subsequently, a comparative analysis of mice with PRNP knockout (KO) vs. wild‑type mice was performed. However, PrP^c depletion did not alter the production of progesterone or estradiol. Whilst the ovarian histology remained intact in KO mice, an elevation in follicle‑stimulating hormone levels was observed, thereby suggesting a potential involvement of compensatory neuroendocrine regulation. These findings revealed that PrP^c may be a novel modulator for maintaining the ovarian reserve which depends on AMH. The present study redefined the molecular landscape of ovarian reserve depletion by identifying the dysfunction of the PrP^c‑AMH axis as a possible reason for diminished ovarian reserve syndromes.

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