Abstract: Objective: To explore the protective effect and molecular mechanisms of noni (Morinda citrifolia) fruit juice on human renal cortical epithelial cells (HK-2) with hyperuricemi. Methods: Morinda citrifolia pulp was prepared and fermented by pectinase and Lactobacillus plantarum to obtain fermented noni juice. Hyperuricemia model of HK-2 cells was established based on by adenosine combined with xanthine oxidase (XO). The cytotoxicity of fermented noni juice on HK-2 cells was detected by CCK-8 experiment. The uric acid content in the supernatant of HK-2 cell culture solution after the treatment of fermented noni juice was detected and the expression levels of hyperuricemia marker proteins urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were detected by Western blotting to verify the regulatory effect of fermented noni juice on HK-2 cells with hyperuricemia. By detecting the expression levels of interleukin-1β (IL-1β) and Tumor necrosis factor-α (TNF-α) in HK-2 cells, the effect of fermented noni juice on inflammatory reaction in HK-2 cells with hyperuricemia was determined. By detecting the expression level of phosphorylated nuclear transcription factor kappa B (NF-κB) p-p65/p65 in HK-2 cells, the regulatory effect of fermented noni juice on NF-κB signaling pathway was verified. Results: When the treatment concentration was lower than 60 μL/mL, the fermented noni juice did not show cytotoxicity. With the treatment of fermented noni juice, the uric acid content which was dose-dependent in the supernatant of cell culture solution was decreased significantly. The expressions of URAT1 and GLUT9 in the experimental group treated with fermented noni juice were significantly lower than those in model group. The fermented noni juice could significantly inhibit the expression levels of IL-1β and TNF-α in hyperuricemia model of HK-2 cell and significantly inhibited the expression of p-p65 in disease model. Conclusion: Fermented noni juice could reduce the content of uric acid in HK-2 cells with hyperuricemia, and then inhibit inflammatory reaction by regulating NF-κB signaling pathway, thus playing a protective role.