By combining comprehensive analysis of CRISPR/Cas9-engineered HCC cell lines with (phospho)proteomics, mouse modeling as well as human patient data, we identified the plakin family member plectin as a novel HCC marker and druggable target upstream of FAK, MAPK/Erk, and PI3K/Akt signaling. Here, AKT1 is linked to hepatocellular carcinoma.