We herein highlighted a newly identified leucine sensor DEPDC5, and elucidated that DEPDC5 knockout rescued apoptotic cell death of HCC induced by leucine depletion whereas DEPDC5 overexpression restrained cell growth in vitro and in vivo, resulting that DEPDC5 could act as a potential tumor suppressor. This evidence concerns the gene DEPDC5 and hepatocellular carcinoma.