Objective:To explore the inhibitory effect and possible mechanism of Hedyotis diffusa polysaccharide(HDP)on human cutaneous squamous cell carcinoma transplanted tumors in nude mice.Methods:25 BALB/cA-nu nude mice were used to establish the transplanted tumor model of human cutaneous squamous cell carcinoma A431 cell line in nude mice.The nude mice with successful modeling(tumor diameter>4 mm after 5 days of inoculation)were randomly divided into 5 groups:nega-tive control group(Con),positive control group[fluorouracil(5-FU)group],low-,medium-and high-dose HDP groups(HDP-L,HDP-M,HDP-H),with 5 mice in each group.The 5-FU group was intraperitoneally injected with 10 mg/kg 5-FU,and the HDP-L,HDP-M and HDP-H groups were intraperitoneally injected with 50,100 and 200 mg/kg of HDP,and the Con group was injected with equal volume normal saline once a day.After 1 month of intervention,the volume,mass and tumor inhibition rate of transplanted tumors in each group were measured.The pathological manifestations were observed by HE staining,and immunohistochemistry was applied to detected the expression of Ki67.The Bcl-2,Bax,p-PI3K/PI3K and p-AKT/AKT were detected by Western blot.Results:HE results revealed that there were different degrees of tumor cell necrosis in various HDP groups and 5-FU group.Compared with Con group,the tumor volume,mass and number of Ki67 positive cells in HDP-M,HDP-H and 5-FU groups were decreased(P<0.05),and the p-PI3K/PI3K,p-AKT/AKT and Bcl-2 were reduced(P<0.05)while the Bax was enhanced(P<0.001).The tumor inhibition rate in 5-FU group was higher than that in the other groups(P<0.05),and the tumor inhibition rate in HDP-H group was higher than that in the other HDP groups(P<0.05).Com-pared with 5-FU group,the tumor volume,mass and number of Ki67 positive cells in HDP-L group were increased(P<0.05),and the p-PI3K/PI3K,p-AKT/AKT and Bcl-2 in tumor tissues in HDP-L and HDP-M groups were risen(P<0.05)while the Bax was lower(P<0.001).Conclusion:Within a certain concentration range,HDP can effectively inhibit the growth of cSCC-A431 transplanted tumors,and its role mechanism may be associated with the suppression of PI3K/AKT signaling pathway ac-tivation,down-regulation of Bcl-2 expression and up-regulation of Bax expression.