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. Here, SQSTM1 is linked to hepatocellular carcinoma.