Our results showed that USP14 was involved in the upregulation of HIF1-α-induced the expression of VEGF, MMP2, or MET. Additionally, USP14 depletion and its inhibitor IU1 significantly inhibited cell proliferation, migration, and angiogenesis in HCC, suggesting that USP14 might be a potential therapeutic target for HCC. This evidence concerns the gene HIF1A and hepatocellular carcinoma.