In the present study, we found sorafenib could induce hypoxia inducible factor (HIF)-2α, which transcriptionally decreased AR expression, whereas HIF-2α Inhibitor, PT-2385, could overcome the side-effects of sorafenib by suppressing HIF-2α and upregulating AR to enhance sorafenib efficacy on HCC invasion via alteration of pSTAT3, pAKT and pERK Signals in vitro and in vivo. Here, EPAS1 is linked to hepatocellular carcinoma.