The evidence of a mechanistic interplay between EYA4 deficiency and NF-κB transactivation-dependent RAP1 up-regulation provided a novel insight for further understanding HCC aggressiveness and might offer a molecular rationale for treating EYA4-deficient and/or NF-κB-hyperactive tumors by interfering with this EYA4-dependent signaling transmission at multiple aspects. This evidence concerns the gene EYA4 and hepatocellular carcinoma.