Polygonum aviculare L. and Its Active Compound Myricetin Inhibit Rheumatoid Arthritis by Targeting Yes

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. In RA, fibroblast-like synoviocytes (FLS) acquire a pathogenic phenotype in response to inflammatory cytokines, promoting synovial inflammation and tissue destruction. Thus, targeting pathological FLS activation has emerged as a promising therapeutic strategy. Herein, we aimed to identify novel plant-derived candidates capable of suppressing synovial inflammation. Screening of 327 plants identified Polygonum aviculare L. (PA) as a potent inhibitor of IL-17-mediated synovial inflammation. PA attenuated IL-17-, TNF-α-, and IL-1β-mediated pathological responses in RA patient-derived FLS (RA-FLS) and alleviated clinical symptoms and histopathological changes in an animal model. Transcriptomic analysis revealed that PA reversed IL-17-induced gene expression and suppressed inflammation-related pathways, with NF-κB emerging as a central regulatory axis. UHPLC-based compound profiling combined with AI-driven bioactivity prediction identified myricetin as an active compound of PA with anti-inflammatory and NF-κB inhibitory activity. Myricetin exerted anti-RA effects in RA-FLS, and both PA and myricetin attenuated synovial inflammation in a 3D synovium-like micromass culture system. PA and myricetin targeted Yes and inhibited its activity, with subsequent suppression of SHP-2 phosphorylation and downstream signaling pathways. Notably, myricetin directly bound to the ATP-binding site of Yes. These findings demonstrate that PA and myricetin inhibit pathogenic responses through the Yes–SHP-2 signaling axis and highlight their potential as plant-derived therapeutic candidates for RA.