Mdm4-Mediated Pfkfb2 Regulates Glucose Metabolic Reprogramming In Oscc

MDM4 is a key negative regulator of the tumor suppressor TP53 gene, yet its functional role in the context of TP53 mutations remains largely unexplored. This study aims to delineate the independent impact of MDM4 on oral squamous cell carcinoma (OSCC) progression and determine the molecular mechanism underlying its regulatory function. This study employed integrative bioinformatics and sequencing analyses combined with quantitative assessments to examine the relationship between TP53 mutations and MDM4 dysregulation in OSCC. Functional investigations in vitro and in vivo evaluated MDM4′s impact on tumor cell proliferation. Metabolomic profiling was utilized to characterize MDM4-mediated metabolic pathway remodeling. Mechanistically, the ubiquitin-proteasome degradation pathway was explored to clarify MDM4′s role in protein stability regulation. Protein-protein interaction networks were identified via immunoprecipitation-mass spectrometry (IP-MS), followed by validation through co-immunoprecipitation and immunofluorescence co-localization to identify specific binding sites. 1.High TP53 mutation rates correlate with MDM4 overexpression in OSCC. 2.MDM4 promotes tumor proliferation and metabolic reprogramming by potentiating the Warburg effect, and PFKFB2 knockdown abolishes MDM4-induced glycolytic activation. 3.MDM4 stabilizes PFKFB2 via YWHAG interaction, maintaining glycolytic homeostasis. MDM4 stabilizes PFKFB2 protein through YWHAG, playing a critical role in promoting the Warburg effect in OSCC cells.