Dual action of baicalin against renal fibrosis in hyperuricemic nephropathy: targeting PANX1-P2Y6 signaling and gut microbiota dysbiosis.

Hyperuricemic nephropathy (HN) is accompanied by persistent hyperuricemia, progressive renal injury, and fibrosis, but effective treatment for the fibrotic component remains limited. Baicalin (BA), a flavonoid isolated from Scutellaria baicalensis Georgi, has been reported to have anti-inflammatory and antioxidant effects, although its role in HN-associated renal fibrosis has not been fully defined. In this study, HN was induced in mice with yeast extract and potassium oxonate, followed by BA treatment. Transcriptomic analysis, molecular docking, molecular dynamics simulation, Western blotting, RT-qPCR, and 16S rRNA sequencing were used to investigate the renal effects of BA and the pathways involved. BA treatment reduced serum uric acid (UA), blood urea nitrogen, and creatinine levels and improved renal histological changes. Fibrotic lesions were also alleviated. At the molecular level, BA decreased transforming growth factor beta 1 (TGF-β1) expression and phosphorylated SMAD family member 3 (p-SMAD3)/SMAD family member 3 (SMAD3) ratio, while pannexin 1/P2Y purinergic receptor 6 (PANX1/P2Y6) signaling and cysteine-aspartic protease 3 (Caspase-3) activation were suppressed. Changes were also observed in the intestinal microbiota, with increased abundance of Lactobacillus and Bacteroides after BA administration. Docking and molecular dynamics analyses further showed favorable and stable interactions of BA with PANX1, TGF-β1, SMAD3, and Caspase-3. These findings suggest that the renal protective effect of BA in HN correlates with inhibition of PANX1/P2Y6-related fibrotic signaling and amelioration of gut microbial dysbiosis, suggesting BA as a potential candidate for reducing hyperuricemia-induced renal injury and fibrosis.