A novel renoprotective mechanism of Phellodendri Chinensis Cortex in uric acid nephropathy: targeting PFKFB3-glycolysis-macrophage axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Phellodendri Chinensis Cortex (PCC), a classic herb for "clearing heat and drying dampness," is traditionally used to treat gout and uric acid nephropathy (UAN) for its urate-lowering and nephroprotective properties. Yet, the mechanism of its direct renoprotective effect remains unclear. AIM OF THE STUDY: This study aims to elucidate the renoprotective efficacy and mechanism of Alkaloids of Phellodendri Chinensis Cortex (APC) in UAN. MATERIALS AND METHODS: UAN rats model was established to assess the hypouricemic and nephroprotective effects of APC. Metabolomic and transcriptomic analyses identified differential metabolites and key pathways. Macrophages polarization markers and glycolysis-related genes were detected by RT-qPCR and immunofluorescence. In vitro, MSU-stimulated THP-1 macrophages treated with APC were used to evaluate glycolytic reprogramming and polarization. Molecular interaction studies were employed to investigate the binding between berberine (BBR) and PFKFB3. Furthermore, Mendelian randomization (MR) analysis and clinical serum samples were used to assess the clinical relevance of PFKFB3, followed by functional validation using serum from UAN patients and PFKFB3 overexpression. RESULTS: APC effectively reduced serum UA and improved renal function, and alleviated renal inflammation and pathological damage in UAN rats. Omics analysis revealed that APC primarily influences the glycolysis pathway, identifying PFKFB3 as a key target. In vivo and in vitro experiments confirmed that APC downregulates PFKFB3, thereby reducing macrophages glycolysis and suppressing M1 polarization. This effect weakened after PFKFB3 overexpression. Moreover, BBR was found to bind directly to PFKFB3 with high affinity. MR analysis supported PFKFB3 as a key mediator of renal impairment for renal impairment, with a significant positive correlation shown with renal dysfunction in clinical serum samples. CONCLUSION: APC mediates renal protection in UAN through a novel mechanism independent of its urate-lowering effect, by directly inhibiting PFKFB3 and thereby regulating the macrophages "glycolysis-polarization" axis.