Polycystic ovary syndrome (PCOS) is related to persistent low-grade inflammation and oxidative stress (OS). Resveratrol (RSV) exhibits potent anti-inflammatory and antioxidant effects, suggesting therapeutic potential for PCOS. However, its precise mechanisms of action, particularly concerning ferroptosis remain unclear. This study aimed to investigate whether RSV ameliorates PCOS by modulating inflammation, OS and ferroptosis features, thereby offering novel insights into its therapeutic role.

PCOS was induced in mice through once-daily subcutaneous dosing of dehydroepiandrosterone (DHEA: 0.6 mg/kg), alongside a 21-day continuous high-fat diet regimen. Following successful model induction, the mice were assigned to the PCOS group or the RSV group. RSV was orally gavaged at doses of 20 and 40 mg/kg/day for 30 days. The body weight, ovarian weight and estrous cycle were monitored. Serum is used for the detection of hormones [follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and inflammatory markers [interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)]. Then the ovarian tissue samples were utilized for the assessment of OS indicators [malondialdehyde (MDA), glutathione (GSH)], glutathione peroxidase 4 (GPX4), and transcriptomic profiling.

RSV was shown to reduce body weight and ovarian weight. RSV also ameliorated symptoms of PCOS by decreasing chronic inflammation, OS and ferroptosis features in the ovaries. All the detected inflammatory factors in the PCOS group were significantly higher than those in the control group (IL-1β, p < 0.0001; IL-6, p < 0.001; TNF-α, p < 0.01) and were significantly decreased with the supplementation of RSV. Ovarian tissue MDA levels were markedly elevated in PCOS mice compared to controls (p < 0.0001), with RSV treatment significantly attenuating this increase. While GSH levels were significantly depleted in PCOS ovaries compared to controls (p < 0.0001), with RSV treatment effectively restoring concentrations. Western blot analysis revealed that GPX4 expression in ovaries was significantly diminished in the PCOS group compared with the control group (p < 0.01), but this reduction was effectively reversed by RSV treatment.

RSV demonstrated therapeutic efficacy in PCOS mice by normalizing hormonal profiles and mitigating chronic inflammatory responses and oxidative damage. Furthermore, our investigation also revealed that RSV ameliorates PCOS pathology by modulating GPX4 pathways, which is consistent with ferroptosis features.