In this study, we reported that MYBL1 enhances the expression of ANGPT2 via directly targeting the ANGPT2 promoter and transcriptionally upregulate ANGPT2 mRNA expression via interacting with PRMT5, MEP50, and WDR5, subsequently promotes HCC angiogenesis and enhanced sorafenib resistance both in vitro and in vivo. This evidence concerns the gene WDR5 and hepatocellular carcinoma.