Exploration of the Potential Mechanism of Clematichinenoside AR in Alleviating Hyperuricemia Based on Untargeted Metabolomics and Nrf2 Signaling Pathway

RATIONALE: Hyperuricemia (HUA) is a metabolic disorder commonly accompanied by oxidative stress and inflammatory responses, which contribute to the progression of kidney and liver injury. Clematichinenoside AR (C-AR), a natural triterpenoid saponin, has been reported to regulate metabolism and exert anti-inflammatory and antioxidant activities. However, its therapeutic potential and underlying mechanisms in HUA remain unclear. METHODS: The anti-hyperuricemic effect of C-AR was evaluated in a mouse model of HUA. Biochemical assays and histopathological analyses were performed to assess uric acid metabolism and organ injury. The expression of inflammation-, oxidative stress-, and urate transport-related factors was determined by RT-qPCR and Western blotting. Untargeted serum metabolomics was conducted using UPLC-Q-TOF-MS/MS to investigate metabolic alterations associated with C-AR treatment. RESULTS: C-AR significantly reduced serum uric acid levels, inhibited xanthine oxidase activity, and alleviated uric acid-induced kidney and liver injury. It suppressed inflammatory responses by decreasing TNF-α, IL-6, and IL-1β levels and attenuated oxidative stress by reducing renal malondialdehyde levels. Furthermore, C-AR upregulated ABCG2, NRF2, and HO-1 expression while downregulating NLRP3 and Caspase-1. Untargeted metabolomics revealed that C-AR predominantly regulated purine metabolism and restored metabolic disturbances associated with HUA. CONCLUSIONS: C-AR effectively ameliorates hyperuricemia by regulating uric acid metabolism, suppressing inflammation, and alleviating oxidative stress. These effects are associated with modulation of the NRF2/HO-1 signaling pathway and purine metabolism, supporting the potential development of C-AR as a natural therapeutic agent for hyperuricemia.