Salidroside Ameliorates Polycystic Ovary Syndrome in Mice by Regulating the AKT/NF-κB/NLRP3-HAS2 Axis

Salidroside, a bioactive compound from Rhodiola rosea, shows potential in managing polycystic ovary syndrome (PCOS), a common endocrine-metabolic disorder. This study explored its therapeutic effects and mechanisms using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model and granulosa cells (GCs). Salidroside was found to restore estrous cyclicity, improve ovarian morphology, and rebalance serum hormone levels. Mechanistically, it suppressed ROS-mediated AKT/NF-κB signaling, inhibited NLRP3 inflammasome activation, and reduced proinflammatory cytokines. Network pharmacology and molecular docking identified AKT as a core target, validated by CETSA and DARTS assays. Furthermore, salidroside disrupted NLRP3-driven latent TGF-β1 (LAP-TGFβ1) activation, downregulated TGF-β-SMAD2/3 signaling, and attenuated ovarian fibrosis along with abnormal hyaluronan synthase 2 (HAS2) expression. These results highlight salidroside as a promising natural candidate for alleviating PCOS through coordinated anti-inflammatory and antifibrotic mechanisms.