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The mechanism underlying the reduction in uric acid levels in hyperuricemia rats by caffeic acid was investigated in this study. Different doses of caffeic acid (25, 50, and 100 mg/kg) were administered to hyperuricemia rats induced by the intraperitoneal injection of potassium oxonate. In vivo study showed that caffeic acid can down-regulate the transcription levels of URAT1 and GLUT9 mRNA and up-regulate the transcription levels of OAT1, UAT, and ABCG2 mRNA. In vitro study indicated caffeic acid competitively binds with xanthine oxidase to inhibit its activity, and the IC50 value was 53.45 µM. It was concluded that caffeic acid decreases serum uric acid levels in hyperuricemia rats by binding with xanthine oxidase and inhibiting its catalytic activity and by regulating the mRNA transcription of the renal uric acid transporters.