PFKFB3, having the strongest phosphofructo-2-kinase activity, is typically up-regulated in cancers including HCC. Overexpression of PFKFB3 and a high flux of glycolysis partly account for sorafenib resistance, which could be targeted by aspirin, as aspirin induces apoptosis together with sorafenib. Elevated levels of PFKFB3 is generally associated with poor outcomes and worse clinical manifestations; therefore, regulating PFKFB3 could not merely inhibit the activity of PFK to target glycolysis, but also arrest cell cycle and cell death in HCC. This evidence concerns the gene PFKFB3 and hepatocellular carcinoma.