Atractylenolide III mitigates polycystic ovary syndrome by activating FDX1-mediated proliferation of ovarian granulocyte cells via PI3K/AKT/mTOR.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder among women of reproductive age worldwide. This study aimed to investigate the therapeutic potential and molecular mechanisms of Atractylenolide III (ATL-III), a bioactive compound derived from Atractylodes macrocephala Koidz., in PCOS. METHODS: Follicular fluid and granulosa cells (GCs) were collected from women with PCOS. A PCOS mice model was established using dehydroepiandrosterone (DHEA). The body weight, estrous cycle, glucose tolerance, insulin tolerance, and ovarian morphology were measured to assess ovarian function. The knockdown and overexpression of ferredoxin 1 (FDX1) were conducted in human granulosa-like tumor cells (KGN). Viability and proliferation of GCs were evaluated by CCK-8 and EdU staining. RT-qPCR, Western blotting, and immunohistochemical staining were performed to detect molecule expressions in the PCOS patients, PCOS mice, and KGN cells. RESULTS: FDX1 expression was significantly decreased in both follicular fluid and GCs of PCOS patients. In PCOS mice, ATL-III was first found that improved the estrous cycle, disordered folliculogenesis, glucose tolerance, insulin resistance, and ovarian morphology, and upregulated ovarian FDX1, and proliferating cell nuclear antigen (PCNA) expression. DHEA-induced KGN cells demonstrated FDX1 suppression associated with proliferation inhibition, whereas FDX1 overexpression rescued proliferative capacity. ATL-III restored KGN cell viability and proliferation through FDX1 upregulation. Mechanistically, ATL-III activated PI3K/AKT/mTOR signaling by regulating FDX1 in both PCOS mice and KGN cells. CONCLUSION: Our findings establish ATL-III as a novel regulator of FDX1 that alleviates PCOS via PI3K/AKT/mTOR-mediated GCs proliferation enhancement, positioning it as a promising therapeutic agent for PCOS treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-025-01941-7.