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

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.

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.

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.

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.