Jiawei Zaoqi Decoction Attenuates Polycystic Ovary Syndrome by Inhibiting AGE-RAGE-Mediated Cell Senescence of Granulosa Cells

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by hormonal imbalances, ovarian dysfunction, and metabolic irregularities. Jiawei Zaoqi Decoction (JWZQD), a Traditional Chinese Medicine (TCM) formulation, has shown potential as a multi-targeted therapeutic intervention for PCOS. However, its underlying mechanisms remain unclear. In this study, we explored the therapeutic effects and molecular mechanisms of JWZQD in managing PCOS. METHODS: We employed a multi-model approach integrating clinical data, animal models, and mechanistic assays. Clinical efficacy was evaluated in a cohort of PCOS patients, while a letrozole-induced rat model combined with a high-fat diet was used to assess reproductive and metabolic outcomes. Network pharmacology, Gene Ontology, KEGG enrichment, and protein-protein interaction analyses were applied to identify key targets and pathways. Granulosa-cell experiments under oxidative stress and insulin stimulation were performed for functional validation. RESULTS: JWZQD administration significantly decreased serum luteinizing hormone and testosterone levels, improved insulin, and restored estrous cyclicity in PCOS patients and rats. Histology and ultrasound revealed reduced cystic follicles and normalized ovarian stroma. Bioinformatic analyses identified cellular senescence and AGE-RAGE signaling as core pathways, with quercetin and fisetin emerging as critical bioactive compounds. In vitro, quercetin and fisetin suppressed senescence markers (p21, p53, γH2AX) and rescued granulosa- cell proliferative capacity, confirming the network predictions. DISCUSSION: These findings provide mechanistic insight into how JWZQD ameliorates PCOS, highlighting its multi-targeted regulation of endocrine, metabolic, and ovarian functions. Importantly, our results suggest that targeting granulosa-cell senescence may represent a novel therapeutic strategy. CONCLUSION: JWZQD mitigates PCOS by modulating AGE-RAGE-mediated granulosa-cell senescence through its active compounds quercetin and fisetin. This study supports the clinical potential of JWZQD as an alternative or complementary therapy for PCOS.