2-ME2 repressed the nuclear translocation of HIF-1α and HIF-2α proteins and significantly weakened the expression levels of both HIF-1α and HIF-2α as well as their downstream targets VEGF, lactate dehydrogenase A, and cyclin D1, enhancing the sorafenib sensitivity of hypoxic HCC cells. This evidence concerns the gene CCND1 and hepatocellular carcinoma.