Fibroblast-like synoviocytes (FLSs) display an aggressive phenotype that is a critical factor in cartilage destruction in rheumatoid arthritis (RA). Increased FLS migration and proliferation are essential to the pathology of RA. Halofuginone has been found to inhibit cell migration and proliferation in cancer cells. However, whether halofuginone has a role in the treatment of RA FLSs is unclear. In this study, we found that halofuginone reduced migration, invasion, cell proliferation and MMPs expression in RA FLSs. In addition, we demonstrated that halofuginone inhibited reorganization of the actin cytoskeleton during cell migration. To gain insight into the molecular mechanisms, we evaluated the effect of halofuginone on the MAPK and ART pathways. Our results indicated that halofuginone inhibited the activity of MAPK and ART. Taken together, these results suggest that halofuginone may protect against joint destruction in RA by regulating synoviocyte migration, invasion and cell proliferation by inhibiting MAPK and AKT activation. (C) 2016 Elsevier B.V. All rights reserved.