Taken together, we examined each step of the cascade from leucine deprivation to poor prognosis of patients with HCC, and elucidated that the DEPDC5-KO HCC cells could acquire anti-oxidant ability through p62 accumulation and survive under leucine starvation, and that downregulated DEPDC5 expression was an independent predictive factor for patient outcome. This evidence concerns the gene DEPDC5 and hepatocellular carcinoma.