In the present study, we demonstrate that UBR7 exerts the tumor suppressive function in HCC through targeting Keap1/Nrf2/Bach1/HK2 axis and aerobic glycolysis, which depends on its E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Here, HK2 is linked to hepatocellular carcinoma.