Corylifol A alleviates rheumatoid arthritis by targeting HSP90α and suppressing Wnt/β-catenin signaling

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Although methotrexate (MTX) remains a first-line therapy for RA, its clinical use may be limited by inadequate response, secondary loss of efficacy, and adverse effects, highlighting the need for safer and more effective therapeutic strategies. Corylifol A (CA), a bioactive monomer derived from traditional Chinese medicine, has been reported to exert immunomodulatory and anti-inflammatory effects; however, its therapeutic role and underlying mechanisms in RA remain insufficiently understood. In this study, THP-1-Lucia™ NF-κB reporter cells were used to screen traditional Chinese medicine-derived monomers with anti-inflammatory potential, and CA was selected for further evaluation in RA fibroblast-like synoviocytes (RA FLSs) and experimental arthritis models. Integrated transcriptomic and network pharmacology analyses were performed to identify the potential molecular targets and pathways involved in the therapeutic effects of CA in RA. CA significantly inhibited the proliferation, migration, invasion, and inflammatory cytokine production of RA FLSs, while alleviating inflammation and bone destruction in arthritic mice. Mechanistically, CA inactivated heat shock protein 90 alpha (HSP90α) and consequently suppressed downstream Wnt signaling. Molecular docking and Asp93 mutation-based rescue experiments further suggested that Asp93 may be involved in the interaction between CA and HSP90α. Moreover, CA enhanced the therapeutic effects of MTX, resulting in more obvious suppression of RA FLSs inflammatory activation and arthritis progression in vivo. These findings suggest that CA may represent a potential therapeutic candidate for RA, and the enhanced therapeutic effects observed with CA plus MTX further support its therapeutic relevance.