Cepharanthine improves rheumatoid arthritis by regulating functions of fibroblast-like synoviocytes and macrophage polarization.

Rheumatoid arthritis (RA) is a chronic autoimmune disease featured by persistent synovial inflammation, progressive bone erosion, and cartilage destruction. Although conventional treatments relieve clinical symptoms, their long-term application is frequently limited by severe side effects. Cepharanthine, a natural alkaloid, possesses potent anti-inflammatory properties, yet its therapeutic effects and precise mechanisms against RA remain largely unclear. This study aimed to evaluate the therapeutic potential of cepharanthine in RA and explore the underlying molecular basis. The effects of cepharanthine were evaluated in interleukin-1 (IL-1) receptor antagonist-deficient (IL1-RA-/-) mice in vivo, and in fibroblast-like synoviocytes (FLS) and RAW264.7 macrophages in vitro. In vivo, cepharanthine significantly decreased the arthritis index and paw swelling, preserved bone microstructure, attenuated synovial hyperplasia and inflammatory infiltration, and mitigated cartilage degeneration in IL1RA-/- mice. In vitro, cepharanthine showed no obvious cytotoxicity at concentrations from 1 nM to 100 μM. Cepharanthine inhibited inflammation, proliferation, and migration of FLS. Meanwhile, cepharanthine promoted the phenotypic shift of macrophages from pro-inflammatory M1 toward anti-inflammatory M2. Transcriptomic profiling and bioinformatics analysis revealed the advanced glycation end products (AGE)-receptor for advanced glycation end products (RAGE) signaling pathway as a key target of cepharanthine. Collectively, cepharanthine mitigates joint inflammation and structural damage in RA by inhibiting the AGE/RAGE/rat sarcoma viral oncogene homolog (Ras)/nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling cascade. Overall, cepharanthine serves as a promising natural candidate for the treatment of RA. This study also provides a novel rationale for developing plant-derived agents against autoimmune arthritis.