Objective To establish an animal model of liver cancer by rapid high-volume tail vein injection，and to investigate the therapeutic effect of O-linked N-acetylglucosamine transferase inhibitor（R）-3-（2methoxyphenyl）-1-（thiophen-2-ylmethyl）piperazine-2，5dione（HLY838） on liver cancer based on the Sleeping Beauty（SB） transposition system. Methods Male C57BL/6J mice，aged 6-8 weeks，were randomly divided into three groups and were given the NRASV12 transposon plasmid，the β-catenin gene-expressing transposon plasmid，or the YAP gene-expressing transposon plasmid pT3-EF1aH Yap S127A，mixed with the transposase SB100 plasmid，through rapid high-volume tail vein injection. The mice were sacrificed after 8-16 weeks of feeding to observe tumor formation and liver pathological changes. After the establishment of the liver cancer model，HLY838 was injected intraperitoneally to investigate its therapeutic effect on liver cancer. Results After high-pressure injection of the plasmids for 8-16 weeks，there was an increase in liver volume，with granular and nodular changes on the surface of the liver，and HE staining showed disordered structure of the liver and the presence of multiple tumor nodules. The pT3-EF1aH YAP S127A group had a higher tumor formation rate and a shorter duration，but with a relatively small tumor size；the pT/CAGGS-NrasV group had moderately sized tumor nodules，but with a relative long time for tumor formation； the pT3-N90-β-catenin group mainly had hepatocellular carcinoma. The HLY838 treatment group had reductions in the number of liver tumor nodules and the burden of liver tumor. Conclusion The method of hydrodynamic high-volume tail vein injection can be used to establish a mouse model of liver cancer rapidly，with a relatively high success rate. The OGT inhibitor HLY838 has a good antitumor effect on liver cancer in mice.