Potentilla freyniana bornm. and its active component tangeretin ameliorate gouty arthritis by inhibiting the MAPK/NF-κb/NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Potentilla freyniana Bornm. (PFB), a medicinal herb from the Rosaceae family, is traditionally used in Traditional Chinese Medicine (TCM) for treating inflammatory conditions, with its rhizome or whole plant commonly prepared as an oral decoction. Gouty arthritis (GA), as a disease typically characterized by inflammatory response, is rising in incidence and prevalence in China-from 122.5 to 151.6 and 640.7 to 810.4 per 100,000, respectively, between 1990 and 2021 (Global Burden of Disease data). Current GA treatments, such as NSAIDs and colchicine, are often associated with adverse effects, underscoring the need for safer alternatives. This study investigates the therapeutic potential of PFB against GA by systematically evaluating its efficacy and underlying mechanisms.

AIMS OF THE STUDY: This study aims to comprehensively investigate the anti-gout effects of the aqueous extract derived from the dried rhizome of PFB, identify its bioactive constituents, and elucidate the underlying mechanisms of action.

MATERIALS AND METHODS: The chemical constituents of PFB aqueous extract were identified using UPLC-Q/TOF-MS, and PFB aqueous extract's therapeutic effects was evaluated in GA mouse model. Mechanistic insights were obtained through integrated network pharmacology and mRNA-seq analyses, with key findings further validated in a mouse air pouch model and an NLRP3-knockout GA model. To identify active components, PFB-derived compounds were screened via molecular docking and molecular dynamics simulations targeting inflammatory proteins; selected candidates showed significant anti-inflammatory effects in the air pouch model and were further validated in vitro.

RESULTS: A total of 36 chemical constituents were identified in PFB aqueous extract. The PFB aqueous extract significantly alleviated GA in mice in a dose-dependent manner, with the highest dose of 560 mg/kg demonstrating the most pronounced effects (p < 0.001). Transcriptomic and network pharmacology analyses revealed that PFB exerts its anti-inflammatory effects by suppressing the MAPK/NF-κB/NLRP3 signaling pathway. This mechanism was validated in an air-pouch model and in the NLRP3-/- gout model, which demonstrated a significant reduction in key inflammatory cytokines (IL-1β, TNF-α, IL18), and contributed to the improvement of synovial and air pouch histopathological features. Additionally, virtual screening pinpointed Tangeretin as the potential candidate with optimal binding affinity and stability. Its anti-inflammatory activity was further validated through in vivo and vitro experiments, showing significant inhibition of inflammatory cytokine and pathways with concentrations as low as 5 μM and achieving strong effects at 20 μM (p < 0.001).

CONCLUSION: The PFB aqueous extract and its active constituent Tangeretin alleviate gouty arthritis by suppressing the MAPK/NF-κB/NLRP3 signaling pathway.