Dual Mechanisms of Naru Sanwei Pills in Gout: NLRP3 Inflammasome Inhibition and Uric Acid Regulation

Purpose: Gout is a metabolic inflammatory disorder driven by monosodium urate (MSU) crystal-induced activation of the NLRP3 inflammasome and frequently accompanied by hyperuricemia-related renal injury. This study aimed to investigate the therapeutic effects of Naru Sanwei Pills (Naru-3) on gout and to elucidate the underlying anti-inflammatory and uric acid-lowering mechanisms. Methods: The anti-gout effects of Naru-3 were initially evaluated in an MSU-induced acute gouty arthritis model (5 days), followed by transcriptomic analysis to investigate the underlying mechanisms. The chemical constituents and potential targets of Naru-3 were subsequently identified through UPLC-Q/TOF-MS, network pharmacology, and molecular docking. Key findings were validated in vivo, including the anti-inflammatory effects of representative compounds in an air pouch model and mechanistic confirmation using gene-deficient mice. Additionally, a potassium oxonate-induced hyperuricemic nephropathy model (28 days) was employed to assess the uric acid-lowering and renoprotective effects. Results: Naru-3 markedly alleviated MSU-induced gouty arthritis by reducing joint swelling, pain hypersensitivity, inflammatory cell infiltration, and IL-1β and TNF-α production. Transcriptomic and pathway enrichment analyses revealed that Naru-3 reversed aberrant activation of the NOD-like receptor and NF-κB signaling pathways. Integrated network pharmacology identified multiple active compounds targeting gout-related proteins, several of which showed strong binding affinity to NLRP3-associated proteins and significant anti-inflammatory activity in vivo. Mechanistically, Naru-3 inhibited NLRP3 inflammasome activation, as confirmed by diminished efficacy in NLRP3- and caspase-1-deficient mice. Furthermore, Naru-3 significantly reduced serum uric acid levels and ameliorated renal injury in hyperuricemic mice by suppressing xanthine oxidase and adenosine deaminase activities and regulating renal urate transporters. Conclusion: Naru-3 exerts dual therapeutic effects against gout by inhibiting NLRP3 inflammasome-mediated inflammation and restoring uric acid homeostasis, supporting its potential as a multitarget therapy for gout and hyperuricemia-related renal injury.