Pomegranate Peel Polyphenol Extract Ameliorates Hyperuricemia by Inhibiting Uric Acid Synthesis and Reabsorption

Hyperuricemia (HUA) is a common metabolic disorder with limited safe and effective therapeutic options. This study integrated GEO dataset mining and network pharmacology to explore the anti-HUA efficacy and mechanism of pomegranate peel polyphenol extract (PPE). In a mouse model of HUA induced by potassium oxonate and 5% fructose water, PPE significantly reduced serum, urinary, and fecal uric acid levels, attenuated the increases in creatinine and blood urea nitrogen, improved estimated glomerular filtration rate, and ameliorated renal pathological damage, inflammation, and xanthine oxidase activity. Integration of GEO-derived HUA-related genes and computational target prediction for PPE identified 44 common targets, and protein-protein interaction network analysis revealed core targets including Akt1. KEGG enrichment highlighted the PI3K-AKT signaling pathway as a key mediator. Western blotting in vivo and in vitro confirmed that PPE suppressed PI3K-AKT phosphorylation and downregulated the urate reabsorption transporters URAT1 and GLUT9. Furthermore, experiments in UA-induced HK-2 cells demonstrated that ellagic acid, a major bioactive component of PPE, acted through the same pathway. These findings indicate that PPE reduces uric acid levels and protects the kidney via modulation of the PI3K-AKT pathway, providing an integrative data-driven rationale for its potential as a functional food or pharmaceutical agent against HUA.