Here, we highlighted that p53 is involved in the modulation of the intracellular copper homeostasis, in hepatoma cell lines, in response to an excessive fat intake through two distinct actions: negatively, acting on SCO2, thus affecting copper excretion, and promoting the up-regulation of CTR1, thus prompting the increase of cellular copper uptake. The gene discussed is TP53; the disease is hepatocellular carcinoma.