In this study, we identified an ANKFN1/ERK/c-Myc/cyclin D1 regulatory axis in HCC cells, in which ANKFN1 promotes HCC cell proliferation by directly or indirectly positively regulating ERK expression; ERK may activate cyclin D1 and Cdk4/6 expression via c-Myc. This evidence concerns the gene MAPK1 and hepatocellular carcinoma.