(1E,4E)-1,5-bis(2-bromo-4,5-dihydroxyphenyl)penta-1,4-dien-3-one alleviates hyperuricemia by inhibiting xanthine...

Hyperuricemia, a metabolic disorder characterized by elevated serum uric acid (SUA) levels, can lead to various complications including gout. Xanthine oxidase (XOD) plays a crucial role in uric acid production and serves as a key therapeutic target for urate-lowering drugs. In this study, we identified (1E,4E)-1,5-bis(2-bromo-4,5-dihydroxyphenyl)penta-1,4-dien-3-one (BPF), a bromophenol derivative, as a potent XOD inhibitor. In vitro, BPF directly bound to XOD, inhibiting its catalytic activity (IC₅₀ = 3.33 ± 0.49 μM) in a reversible and mixed mode (K_i = 0.80 μM; K_i' = 6.06 μM). Molecular docking and dynamics simulation suggested that BPF stably bound to the molybdenum center and key amino acid residues (such as Glu⁸⁰², Glu⁸⁷⁹, and Val¹⁰¹¹) of XOD. In hyperuricemic mice, BPF effectively suppressed uric acid production via inhibiting hepatic XOD activity. In addition, BPF exhibited the potential to promote uric acid excretion by upregulating ABCG2 and downregulating GLUT9. As a result, BPF significantly reduced SUA and improved renal function. In summary, our findings demonstrated that BPF reduced uric acid by inhibiting XOD activity and exhibited good in vivo safety, supporting its further development as a potential treatment for hyperuricemia.