Abstract: Objective: To investigate the mechanism underlying the uric acid-lowering effect of Limosilactobacillus fermentum FOSU-YHD19 (L. fermentum YHD19) at the cellular level. Methods: A hyperuricemic cell model was established using HK-2 cells. The cells were treated with gradient concentrations of L. fermentum YHD19 (105–109 CFU/mL). Its cytotoxicity was assessed by the CCK-8 assay, and its inhibitory effects on the expression levels of urate transporters and the inflammatory response were detected. The uric acid-lowering effect and biosafety of the strain were systematically evaluated. Results: At all tested concentrations, L. fermentum YHD19 exhibited no significant cytotoxicity toward HK-2 cells. Also, the strain was found to inhibit the expression of urate transporter 1 and glucose transporter 9, both related to urate reabsorption, and upregulate the expression of the key urate efflux transporter, ATP-binding cassette subfamily G member 2 (ABCG2), consequently maintaining uric acid homeostasis, with a more pronounced regulatory effect on uric acid metabolism observed at higher concentrations (109 CFU/mL). Furthermore, L. fermentum YHD19 significantly reduced the expression levels of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and phosphorylated (p-p65), by blocking the activation of the nuclear factor kappa-B (NF-κB) signaling pathway, thereby effectively alleviating the hyperuricemia-induced inflammatory response. Conclusion: L. fermentum YHD19 demonstrates good safety and can exert its uric acid-lowering effect through multiple synergistic signaling pathways. It has potential application value in the prevention and adjuvant therapy of hyperuricemia.

Key words: hyperuricemia; lactic acid bacteria; HK-2 cells; uric acid transporter; nuclear factor kappa-B signaling pathway