Luteolin alleviates PCOS by inhibiting AR/STAT3/NLRP3-mediated granulosa cell pyroptosis.

Abstract

BACKGROUND: Polycystic ovary syndrome (PCOS), a common endocrine-metabolic disorder, is driven by hyperandrogenism and chronic low-grade inflammation that impair follicular development. Granulosa cell pyroptosis is increasingly recognized as a key pathogenic mechanism in PCOS. Luteolin (LUT), a natural flavonoid found in many traditional medicinal plants, exhibits potent anti-inflammatory properties. However, its role in regulating granulosa cell pyroptosis within the context of PCOS has not been elucidated. METHODS: We established a dehydroepiandrosterone (DHEA)-induced PCOS rat model to evaluate LUT's therapeutic effects. Hormone and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA), while network pharmacology and molecular docking were used to predict molecular targets. In vitro, dihydrotestosterone (DHT)-treated KGN cells served as a model for granulosa cell dysfunction. Pyroptosis was assessed by Cell Counting Kit-8 (CCK-8), lactate dehydrogenase (LDH) release, and transmission electron microscopy. The expression and activation of androgen receptor (AR), Signal Transducer and Activator of Transcription 3 (STAT3), and NOD-like Receptor Pyrin domain-containing protein 3 (NLRP3) inflammasome components were analyzed by Western blot and immunohistochemistry, with their roles confirmed using specific inhibitors. RESULTS: Luteolin (LUT) treatment alleviated hormonal imbalance and ovarian morphological abnormalities in PCOS rats. LUT suppressed STAT3 phosphorylation, pro-inflammatory cytokine expression, and NLRP3 inflammasome activation in both in vivo and in vitro models. Network pharmacology identified STAT3 as a high-affinity target of LUT (binding energy: - 8.589 kcal/mol). Mechanistically, LUT attenuated granulosa cell pyroptosis by suppressing the AR/STAT3/NLRP3 axis. CONCLUSION: Luteolin inhibits androgen-induced granulosa cell pyroptosis by targeting the AR/STAT3/NLRP3 signaling pathway. These findings provide a robust mechanistic basis for luteolin's therapeutic potential in PCOS, supporting its development as a targeted therapy for this and other inflammatory reproductive disorders.