Potential therapeutic benefits of Murraya exotica L. extract on type II collagen-induced arthritis

Rheumatoid arthritis (RA) is a chronic progressive autoimmune condition marked by persistent synovial inflammation, pannus development, bone erosion, and eventual joint deterioration. Murraya exotica L. (ME), a botanical source of Murrayae Folium et Cacumen (MFC), remains unexplored for its anti-arthritic potential, motivating this study. The composition of ME was characterized using ultra-performance liquid chromatography (UPLC) techniques, while its anti-arthritic effects were evaluated in collagen-induced arthritis (CIA) rats and interleukin (IL)-1β-triggered SW982 cells. The contents of meranzin hydrate, hainanmurpanin, murrayone, and 3',4',5,5',6,7-hexamethoxyflavone in ME extract were quantified to be 2.86 ± 0.01%, 1.88 ± 0.01%, 0.07 ± 0.00% and 0.01 ± 0.00%, respectively. In CIA rats, ME alleviated clinical symptoms, attenuated histopathological joint damage (synovial hyperplasia, cartilage degeneration, and bone erosion), ameliorated inflammation, and reduced oxidative stress. In IL-1β-stimulated SW982 cells, ME inhibited proliferation/migration, suppressed inflammatory response, and mitigated oxidative stress. Network pharmacology and molecular docking predicted strong interactions between ME-derived compounds (e.g., murrayone) and NF-κB p65, further validated by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Mechanistically, ME blocked nuclear factor-kappa B (NF-κB) activation via inhibition of the inhibitor of NF-κB-α (IκBα) phosphorylation/degradation and p65 nuclear translocation, while suppressing activator protein-1 (AP-1) activation through downregulation of c-Fos/c-Jun. Pharmacological inhibitors (pyrrolidinedithiocarbamate (PDTC) for NF-κB; SR11302 for AP-1) further confirmed the involvement of NF-κB and AP-1 pathways in ME-mediated anti-inflammatory, anti-proliferative, and anti-oxidative actions in RA.