To conclude, by employing a multi-omics approach, we investigated protein-level aberrations showing limited DNA or RNA level alterations in two human HCC cohorts and identified potential therapeutic targets showing expression-driven dependency upon targeting inhibitory treatment in human HCC cell lines; FGFR4 kinase and Hsp proteins, lacking actionable mutations, may be targetable in a fraction of HCC as supported by the vulnerability exposed by their respective targeting inhibitors. Here, HSP90B2P is linked to hepatocellular carcinoma.