Abstract Background Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune inflammatory disease. Bi Zhong Xiao decoction (BZXD) performs multiple functions for rheumatoid arthritis (RA) treatment for decades. In this study, we aimed to study the protein alterations of BZXD in the early and late stages of RA. Methods Sprague–Dawley rats were randomly divided into the Control, collagen-induced arthritis (CIA) and BZXD groups. Clinical assessment, paw thickness, weight changes and serum inflammatory cytokine levels were used to evaluate anti-inflammatory effects. Histopathological tests were performed to assess the improvement of inflammation and synovial hyperplasia. Moreover, we analyzed the proteins profiling of synovial tissue samples with different time intervals after BZXD treatment by Isobaric Tag for Relative Absolute (ITRAQ) quantitative proteomics technology. To further explore the interrelationships among differentially expressed proteins (DEPs), we used DAVID Bioinformatics Resources v6.8 and STRING 11.0 for bioinformatics analysis. Besides, the western blot and immunohistochemistry were exerted to verify related proteins. Results In our study, BZXD ameliorated joint inflammation, and suppressed the pathological changes in arthrosis of CIA rats. The proteomic analysis demonstrated that CIA rats were mainly involved in two significant pathways (the focal adhesion and the ECM-receptor interaction) in the early stage. BZXD down-regulated the expression of proteins involved in these pathways, such as CAV1, CHAD, COL3A1, COL5A2, COL6A1, and COL6A5. Additionally, BZXD exerts anti-inflammatory effects in the late stage mainly by increasing the expression of FASN and affecting fatty acid metabolism. Conclusion BZXD exerts therapeutic effects on RA through multi-pathways in the early and late stages. This work may provide proteomic clues for treating RA by BZXD.
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