Dapansutrile Mitigates DHT-Induced Polycystic Ovary Syndrome by Suppressing NLRP3 Inflammasome and TLR4/NF-κB Signaling

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This study investigated the therapeutic effects of Dapansutrile, a selective NLRP3 inflammasome inhibitor, on ovarian dysfunction in a dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS) rat model. Thirty adult female Wistar rats were allocated to control, PCOS + saline, and PCOS + Dapansutrile groups. PCOS was induced by subcutaneous DHT pellet implantation, followed by 28 days of intraperitoneal saline or Dapansutrile (100 mg/kg/day). Ovarian histology (follicle counts, fibrosis) and biochemical parameters (hormones, inflammatory and oxidative markers) were assessed. DHT exposure disrupted folliculogenesis, reducing primary (P < 0.001), secondary (P < 0.001), and tertiary follicles (P = 0.004), and markedly increased fibrosis (P < 0.001). Dapansutrile significantly enhanced primary (P < 0.01) secondary (P < 0.05) and tertiary follicle counts (P < 0.05), alleviated ovarian fibrosis (P < 0.001). Biochemically, PCOS rats exhibited elevated AMH, IGF-1, TNF-α, TLR4, MyD88, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, and TGF-β1, alongside depleted ovarian GSH. Treatment with Dapansutrile attenuated inflammatory and fibrotic markers, elevated GSH, and decreased AMH and IGF-1, without altering insulin levels. Collectively, these findings provide the first evidence that Dapansutrile alleviates PCOS-induced ovarian dysfunction by suppressing inflammasome-driven inflammation, oxidative stress, and fibrosis, thereby improving follicular maturation and reducing stromal fibrosis in a hyperandrogenic PCOS model.

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