In the present study, we provide evidence that high MARCH5 accompanied by increased autophagy is associated with malignant progression of liver tumors and low survival in HCC patients and reveal that MARCH5 promotes autophagy through ubiquitinated p53 leading to tumor cell proliferation.Thus, our mechanistic studies and clinical data strongly suggest that MARCH5 is an important player in hepatocarcinogenesis. This evidence concerns the gene MARCHF5 and hepatocellular carcinoma.