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The discovery of new therapeutic drugs with the ability of preventing inflammation and joint destruction with less adverse effects is extremely urgent for rheumatoid arthritis (RA).Cryptotanshinone(CTS), an active component isolated from the root ofSalvia miltiorrhizaBunge, has been reported to have antibacterial and antitumor effects. However, its effects on RA have not been clearly elucidated. Here, we investigated the therapeutic effect of CTS on type II collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms. Our results revealed that CTS treatment efficaciously ameliorated inflammation and joint destruction of rats with CIA. Both in vivo and in vitro studies showed that CTS suppressed the production of proinflammatory cytokines including interleukin 1β, tumor necrosis factor alpha, and interleukin 17α production and downregulated the production and activity of matrix metalloproteinase 9. By receptor activator of nuclear factor kappa B (NF-κB) ligand–induced bone marrow macrophages, we observed that CTS could inhibit osteoclast differentiation, which is critic for joint destruction. Further studies on inflammatory signaling revealed that CTS could inhibit the degradation of inhibitor of NF-κB (IκB) α in vivo and in vitro, prevent the nuclear translocation of NF-κB p65 induced by lipopolysaccharide in a time- and dose-dependent manner. By electrophoretic mobility shift assay and luciferase reporter assay, we found that CTS distinctively inhibited the NF-κB DNA binding activity and NF-κB–dependent luciferase activity. These results indicate that the therapeutic effect of CTS on CIA is accomplished mainly through the inhibition of NF-κB signaling. Our findings provide the evidence to develop CTS as a potential therapeutic agent for patients with RA.