Daidzein Ameliorate Hyperuricemia by Upregulating ABCG2 Expression via Activation of PPARγ and PI3K/AKT Pathways

ABSTRACT Hyperuricemia is a chronic metabolic disorder characterized by the excessive accumulation of serum uric acid. This condition exhibits a notable gender disparity in its prevalence. Soybean‐derived flavonoids, classified as phytoestrogens, have been reported to exert anti‐tumor, hypoglycemic, and anti‐atherosclerotic effects. However, their effect on hyperuricemia remains unclear. In this study, using potassium oxonate and adenine‐induced hyperuricemia mice, we found that both soy isoflavones and the major constituent daidzein significantly reduced serum uric acid levels, improved hepatic and renal function markers, and up‐regulated the expression of ABCG2 in kidneys and intestines. Histopathological analysis revealed that both treatments conferred potent hepatorenal protection, with a potency surpassing that of estradiol. In vitro, daidzein up‐regulated ABCG2 expression through the activation of the PI3K/AKT and PPARγ signaling pathways in HK‐2 and Caco‐2 cells. Collectively, these findings demonstrate that soy isoflavones and daidzein promote uric acid excretion by enhancing renal and intestinal ABCG2 expression, highlighting their potential as dietary supplements or therapeutic agents for hyperuricemia management.