MDMX reprograms glycolysis of hepatocellular carcinoma via 14-3-3γ/FOXO1

Abstract MDMX serves as a significant regulator of p53, which is a crucial tumor suppressor protein. However, the biological functions and underlying mechanism of MDMX in hepatocellular carcinoma (HCC) remain inadequately understood. In this study, we demonstrate that MDMX is overexpressed in HCC, and elevated expression of MDMX is significantly correlated with poor prognosis in HCC harboring mutant p53. MDMX inhibits the degradation of 14-3-3γ and facilitates its localization within cytoplasm, thereby enhances the interaction between FOXO1 and 14-3-3γ, which promotes the degradation of FOXO1. Consequently, the overexpression of MDMX results in downregulation of FOXO1 followed by increase of RPIA and decrease of PCK1, leading to increased glucose uptake, lactate secretion, and ATP production. These findings elucidate the role of MDMX in promoting glycolysis through the regulation of the 14-3-3γ/FOXO1 axis in p53-mutated HCC, thereby offering a potential therapeutic target for the treatment of HCC.