In HCC, treatment with sorafenib would lead to a hypoxic tumor microenvironment [Sorafenib-induced hypoxia (SIH)] due to pericyte depletion and reduction of tumor vessels, while SIH further promoted the accumulation and stabilization of HIF-1α and HIF-2α, leading to oncogene transcription and angiogenesis, which promoted the resistance of HCC cells to sorafenib (Cooke et al., 2012; Dong et al., 2018; Song et al., 2019). Here, EPAS1 is linked to hepatocellular carcinoma.