Natural Polyphenol Pentagalloyl Glucose as a Potent Xanthine Oxidase Inhibitor for Hyperuricemia Treatment

Hyperuricemia (HUA) is a metabolic disorder characterized by increased serum uric acid (UA) levels. Here, we showed that pentagalloyl glucose (PGG), a well-known natural polyphenol, significantly decreased UA levels both in potassium oxonate/hypoxanthine-induced HUA mice and adenosine-induced hepatocytes. Mechanistically, the UA-lowering effect of PGG was attributed to the suppression of UA formation by inhibiting xanthine oxidase (XOD) activity and expression. PGG acted as a reversible mixed-type inhibitor of XOD (IC₅₀ = 3.92 ± 0.06 μM), and its binding was driven primarily by hydrogen bonding and van der Waals forces. Structural analyses revealed PGG occupied the catalytic center of XOD, obstructing xanthine binding and inducing conformational changes. Integrated kinetics, isothermal titration calorimetry, multispectroscopic investigations, and computer simulations confirmed these interactions. These findings first comprehensively suggest the anti-HUA effect of natural XOD inhibitor PGG and highlight the promising potential of PGG as a functional food or drug candidate for treating HUA-related diseases.