〔Abstract〕 To explore the therapeutic mechanism of puerarin in treating rheumatoid arthritis (RA) rats based on the serine/tyrosine protein kinase B (AKT)-phosphorylated forkhead box protein O1 (FOXO1)-interleu- kin-9 (AKT-FOXO1-IL-9) signaling pathway . Methods 36 rats were randomly divided into a blank group , a model group , a positive control group , and low , medium , and high dose groups of puerarin . Except for the blank group , the other groups were induced with type Ⅱ collagen to establish a RA rat model . After successful modeling , different doses of puerarin and methotrexate were given to treat the rats . The body mass and toe thickness of the rats were measured , and biochemical indicators of rat blood rheology were detected . X-ray was used to observe changes in rat joint morphology . Safranin green staining were used to observe the pathology of rat joint tissue . ELISA was used to detect the levels of IL-9 and rheumatoid factors in rat serum , and Western blot was used to detect changes in levels of AKT and FOXO1 . Results Compared with the blank group , the model group had the lowest toe thick- ness , and X-ray images showed more obvious segmental stenosis and more severe marginal bone invasion; scaly like changes appeared at the edges of joints stained with safranin green , accompanied by the exudation of inflammatory cells and increased proliferation and secretion of chondrocytes; the expression levels of inflammatory factors IL-9 and rheumatoid factors were the highest , and the expression levels of AKT and FOXO1 proteins were the highest (P < 0. 05) . Compared with the model group , the toe thickness of rats treated with different doses of puerarin de- creased ; X-ray images showed that the puerarin treatment group of rats showed improvement in plantar joint stenosis and marginal bone invasion; the results of safranin green staining showed that after treatment with different doses of puerarin , the infiltration of inflammatory cells decreased , and the expression levels of inflammatory factor IL-9 , rheumatoid factors , AKT , and FOXO1 proteins decreased significantly ( P < 0. 05) , with the high-dose puerarin group showing the most significant difference . Compared with the high-dose puerarin group , the positive control group showed a significant decrease in the above results and statistical differences (P < 0. 05) . Conclusion Puer- arin has a good therapeutic effect on rats with RA by inhibiting the AKT-FOXO1-IL-9 pathway . The high-dose pu- erarin group (60 mg/kg) has the best therapeutic effect and the results show a dose-response relationship .