Abstract: OBJECTIVE To investigate the effects of cinobufotalin on the tumor markers, immune function and expression of PI3K/AKT signaling pathway protein in lung cancer model rats. METHODS Eighty Wistar rats were randomly divided into control group, model group, cinobufagin group and cyclophosphamide group, 20 rats in each group. Lung cancer rat model were established by injected with carcinogenic iodized oil solution. The histopathological morphology, serum levels of carcinoembryonic antigen(CEA), carbohydrate antigen-125(CA125) and neuron-specific enolase(NSE), content of CD3⁺, CD4⁺, CD8⁺ and NKT cells, expressions of AKT-1, Cyclin D1, NF-κB mRNA, PI3K and p-AKT proteins were compared at the 4th and 8th weeks respectively. RESULTS The body weight of rats in cinobufotalin group decreased at first, then increased gradually after 3 weeks, and cyclophosphamide group decreased at first, and increased after 4 weeks. The volume and weight of tumors in cinobufotalin group and cyclophosphamide group were decreased significantly, and the inhibition rate were increased significantly(P<0.05). The swelling of lung tissue was not obvious, and pathology obviously and the structure of alveolar sac and epithelial cells was basically clear in cinobufotalin group and cyclophosphamide group. The serum CEA, CA125 and NSE levels in cinobufotalin group and cyclophosphamide group were significantly reduce, the content of CD3⁺, CD4⁺ were increased significantly, the content of CD8⁺ and NKT cells were lower, the expression of AKT-1, Cyclin D1, NF-κB mRNA were significantly reduce, the expression of PI3K and p-AKT protein were significantly reduce, and the 8th week was better than that of the 4th week(P<0.05). CONCLUSION Cinobufotalin can increase the body weight, decrease the volume and weight of lung cancer, increase the inhibition rate, improve the tumor markers and immune function of lung cancer model rats. The mechanism may be related to the decrease of AKT-1, Cyclin D1, NF-κB mRNA level and PI3K, p-AKT protein expression.