Moreover, since sorafenib could not create hypoxic microenvironment in intro, the potential other pathways sorafenib regulated inducing autophagy were also effectively inhibited by FOXO3a, which suggested FOXO3a is a common deep downstream factor in regulating autophagy in sorafenib-treated HCC and targeting FOXO3a could be a more promising approach to reverse clinical sorafenib resistance. This evidence concerns the gene FOXO3 and hepatocellular carcinoma.