Gnetum Montanum Markgr. Extract mitigates gouty arthritis by targeting urate crystal-induced NLRP3 inflammasome activation.

Abstract

Gouty arthritis is a common metabolic disorder characterized by the deposition of monosodium urate (MSU) crystals in joints. Aberrant activation of the NLRP3 inflammasome is a key driver of MSU-induced joint inflammation, making it a promising therapeutic target for gouty arthritis. Gnetum montanum Markgr. has long been used in traditional medicine in parts of Asia to treat gout; however, its effects on gout-specific inflammatory responses have not been fully elucidated. In this study, we used two cell models, including MSU-stimulated mouse primary peritoneal and THP1 derived macrophages, in combination with western blot analysis, enzymatic activity assays, ELISA method, and flow cytometry analysis to evaluate the protective effect of G. montanum extract (GME) against MSU-driven inflammation. A mouse model of MSU-induced paw edema was then employed to validate the in vivo anti-inflammatory efficacy. We found that GME alleviated gouty inflammation by inhibiting NLRP3 inflammasome activation in mouse peritoneal and human THP-1 macrophages. GME also protected macrophages from MSU-induced pyroptosis, a pro-inflammatory form of programmed cell death. Mechanistically, GME suppressed xanthine oxidase (XO) activation triggered by MSU crystals, resulting in decreased reactive oxygen species (ROS) production. This reduction in ROS prevented the upregulation of thioredoxin-interacting protein (TXNIP), a key mediator that binds to and activates NLRP3. Furthermore, oral administration of GME in mice attenuated MSU-induced paw inflammation, likely through downregulation of XO-driven oxidative stress and NLRP3 inflammasome signaling. These findings suggest that GME effectively modulates gout-specific inflammatory pathways and warrants further investigation of GME as a potential therapeutic candidate for gouty arthritis.