Targeting the gut-ovarian axis: Scutellaria baicalensis improves polycystic ovary syndrome by modulating gut microbiota composition and inhibiting the LPS/TLR4/NF-κB signaling pathway.

Polycystic ovary syndrome (PCOS) is a chronic inflammatory disease caused by a combination of genetic, environmental, and gut microbiota factors. Western medicines can improve ovulation rates, but are linked with reduced pregnancy success and side effects. Scutellaria baicalensis (BAL) is a famous anti-inflammatory Chinese herb, which has therapeutic effects for PCOS; however, the mechanism remains unclear. This study integrated network pharmacology, molecular docking, and animal experiments to investigate the mechanisms by which BAL improves gut microbiota and intestinal inflammation in a rat PCOS model. We identified 36 active components of BAL, including wogonin, baicalein, and oroxylin A, along with 145 potential targets, such as TNF, IL-6, and AKT1, and network analysis revealed that TNF, IL-6, and AKT1 occupied central positions. Enrichment analyses indicated that BAL may exert its therapeutic effects by modulating the NF-κB and Toll-like receptor signaling pathways. Molecular docking results demonstrated strong binding affinities between BAL's primary active components and the core targets TNF, AKT1, and IL-6. BAL experiments in PCOS rats showed that it restored gut microbiota balance. These results showed that BAL inhibits the LPS/TLR4/NF-κB pathway and downregulates PI3K and p-Akt/Akt protein expression in ovarian tissue. BAL also improved reproductive metabolic abnormalities, intestinal inflammation, and dysbiosis. Our study suggests that BAL inhibits the LPS/TLR4/NF-κB pathway via the gut-ovarian axis, regulating gut microbial composition and alleviating inflammatory states. This may be a mechanism for the therapeutic efficacy of BAL for PCOS and a novel therapeutic strategy for the clinical management of polycystic ovary syndrome.IMPORTANCEPCOS affects women of reproductive age. Current clinical treatment strategies still face limitations in efficacy and long-term side effects. This study employs network pharmacology, molecular docking, and experimental validation to elucidate the mechanism by which the traditional Chinese medicine BAL improves PCOS. We found that BAL modulates gut microbiota in a PCOS rat model, significantly increasing the probiotic genus Phocaeicola. This change correlates with reduced serum LPS levels and alleviated ovarian inflammation. Experiments confirm that BAL alleviates local ovarian inflammation and insulin resistance by inhibiting the LPS/TLR4/NF-κB signaling pathway, thereby improving PCOS pathological manifestations. This study reveals new mechanisms of BAL in treating PCOS and highlights the potential bridging role of probiotics like Phocaeicola. It also provides experimental evidence and theoretical support for integrated Chinese and Western medicine treatment strategies based on regulating gut microbiota.