Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and hyperplasia. The complexity of pathway networks within RA has not been well defined. To discover the pathway networks that were involved in RA pathological process and investigate the pathogenesis of RA, iTRAQ-based quantitative proteomics was used in a collagen-induced arthritis (CIA) model at days 28 and 42 of RA. The data were analyzed using Ingenuity pathway analysis (IPA) software. 69 proteins were repeatedly identified at both time points (days 28 and 42) in the CIA model. 5 proteins (MMP3, APOE, ASPN, LIFR, SERBP1) showed progressive changes in expression. IPA revealed 14 proteins involved in connective tissue disorders. ACLY, A1BG, CA3, FTH1, and FTL have been found associated with "rheumatic disease" and "arthritis" in CIA model for the first time. LXR/RXR activation in CIA model was first discovered in IPA pathway analysis. Network analysis revealed several focus proteins in the four significant networks. The progressively changed proteins, MMP3, APOE and ASPN, LIFR, SERBP1, may be correlated with RA disease severity and confirmed by WB and IHC. The findings will provide a new range for elucidation of the pathogenesis of RA in the near future. This journal is