The alkaloid-rich extract of Piper sintenense Hatusima alleviates gouty inflammatory response via Nrf2-mediated antioxidant induction.

Gouty arthritis (GA), a common inflammatory arthropathy characterized by monosodium urate crystal deposition in joints and soft tissues, currently lacks safe and effective therapeutic agents. Piper sintenense Hatusima, a plant used for both medicinal and dietary purposes, is widely utilized in ethnic minority regions of China and is believed to alleviate joint swelling and pain. This study aims to identify the active components of P. sintenense responsible for its anti-GA effects, and to investigate their composition and underlying mechanisms. Our results demonstrated that the alkaloid fraction (PAL) serves as the primary active component for treatment of GA in P. sintenense. In both rats and mice GA animal models, administration of PAL led to reduced serum levels of inflammatory factor tumor necrosis factor-α (TNF-α) and increased levels of anti-inflammatory factor transforming growth factor-β (TGF-β). PAL treatment also reduced serum uric acid and creatinine levels, alleviated pain-related gait abnormalities in GA model animals. Piperine, pipernonaline, and dehydropipernonaline were identified as the major constituents in PAL. Network pharmacology and experimental validation revealed that PAL can suppress reactive oxygen species (ROS) and malondialdehyde (MDA) levels, enhance glutathione (GSH) release in the GA model. Furthermore, Western blot analysis indicated that the PAL promotes Nrf2/HO-1 protein expression and inhibits the release of inflammatory cytokines, exerting anti-GA effects. These effects were reversed upon administration of the Nrf2-specific inhibitor ML385. These findings suggest that PAL are the principal bioactive constituents in P. sintenense responsible for its therapeutic effects against GA. PAL activate the Nrf2/HO-1 signaling pathway, which subsequently alleviates oxidative stress and contributes to the anti-GA effects.