Hexokinase (HK), the first glycolytic pathway enzyme, can be upregulated by hypoxia, which is associated with HCC resistance to regorafenib.277 Mechanistically, hypoxia stabilizes HIF-1α by ubiquitin-specific peptidase (USP29) and then transcriptionally activates HK.278 Pyruvate kinase M2 (PKM2), another rate-limiting enzyme of glycolysis, is overexpressed in TKI treatment, accompanied by high levels of lactate production. The gene discussed is HIF1A; the disease is hepatocellular carcinoma.