Our results show that knockdown of URGCP/URG4 effectively decreases the phosphorylation of FOXO3a and subsequently inhibits G1-S transition, through upregulation of the CDK inhibitors p21Cip1 and p27Kip1, while downregulating cyclin D1, thus providing new insights into the role of URGCP/URG4 in HCC development and progression associated with HBV or HBx. Here, FOXO3 is linked to hepatocellular carcinoma.