Using transcriptomics [RNA sequencing (RNA-seq)], epigenetics [chromatin immunoprecipitation sequencing (ChIP-seq)], and proteomics [liquid chromatography tandem mass spectrometry (LC-MS/MS)] profiling followed by validation assays, our study collectively revealed that ACTR5 is required for CDKN2A silencing and CDK6/E2F1-mediated cell cycle progression in HCC. This evidence concerns the gene E2F1 and hepatocellular carcinoma.