Protective Effects of Oxyberberine Against Hyperuricemic Nephropathy: Mechanistic Insights From In Silico, In Vitro, and In Vivo Studies

Oxyberberine (OBB), a key metabolite of berberine (BBR), has exhibited enhanced pharmacological efficacy compared to BBR. Nonetheless, the potential of OBB in the treatment of hyperuricemic nephropathy (HN) warrants further investigation. Therefore, this investigation focused on elucidating the therapeutic efficacy and underlying mechanism of OBB in counteracting HN. An HN mouse model was established for in vivo study, while uric acid (UA)-stimulated human renal tubular epithelial cells (HK-2) were used for in vitro evaluation. Bioinformatics and molecular docking analyses were also employed. Bioinformatics analysis and molecular docking results underscored the critical involvement of the NLRP3 axis in mediating the protective effects of OBB against HN. In vivo, OBB treatment significantly reduced kidney weight and index, improved renal function, and mitigated abnormal histopathological alterations. Moreover, OBB lowered MDA, ROS, IL-1β, IL-18, and TNF-α levels, along with enhanced SOD and CAT activities, both in vitro and in vivo. Mechanistically, OBB markedly lowered serum UA levels by increasing the expression of organic cation transporter 1/2 (OCT1/2) and organic cation/carnitine transporter 1/2 (OCTN1/2) at both transcriptional and translational levels. Additionally, OBB markedly reduced the expression of Keap1, TXNIP, NLRP3, ASC, Caspase-1, and GSDMD-N, while promoting Nrf2 nuclear translocation and enhancing the protein expression of HO-1, NQO1, CAT, SOD1, GCLC, and GPX4. Our results for the first time indicated that OBB treatment exerted a significant anti-HN effect. It reduced serum UA level by modulating the OCTs and OCTNs, a mechanism distinct from that of current first-line agents. Additionally, OBB alleviated renal damage through the modulation of the Keap1/Nrf2-NLRP3 axis.