• OXH suppresses LPS-induced inflammation in macrophages by inhibiting the TLR4-MD2/NF-κB/MAPK signaling axis.
• OXH directly binds to the TLR4/MD2 complex with a Kd of 33.7 μM, competing with LPS for binding.
• In a rat CIA model, OXH ameliorates arthritis symptoms, reducing joint swelling, bone erosion, and pro-inflammatory cytokine expression.
• OXH represents a promising natural compound for RA therapy with a novel mechanism targeting the TLR4-MD2 complex.