Paeoniflorin-6’-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability,as well as better anti-inflammatory activity than its parent compound.In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors-mediated signaling pathways.CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days.In CIA mice,we found that T cells and B cells exhibited abnormal proliferation;the percentages of CD19+ total B cells,CD19+CD27+-activated B cells,CD19+BAFFR+ and CD19+TACI+ cells were significantly increased in PBMCs and spleen lymphocytes.CP-25 suppressed the indicators of arthritis,alleviated histopathology,accompanied by reduced BAFF and BAFF receptors expressions,inhibited serum immunoglobulin levels,decreased the B-cell subsets percentages,and prevented the expressions of key molecules in NF-κB signaling.Furthermore,we showed that treatment with CP-25 reduced CD19+TRAF2+ cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro.Thus,CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels,and normalized the elevated levels of IgA,IgG2a and key proteins in NF-KB signaling.In comparison,rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25;they suppressed the elevated inflammatory indexes to below the normal levels in ClA mice.In summary,our results provide evidence that CP-25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF-KB signaling.CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.