Abstract

Despite therapeutic advances, esophageal squamous cell carcinoma (ESCC) remains lethal due to metabolic adaptation via aerobic glycolysis. Here we report that VAV2 functions as an oncoprotein promoting this metabolic switch in ESCC. VAV2 overexpression enhances glycolytic flux—evidenced by increased glucose uptake, lactate production, and ECAR—while reducing oxygen consumption. Mechanistically, VAV2 upregulates EIF3F expression, enabling EIF3F to deubiquitinate and stabilize MTA1, which subsequently activates HIF-1α and its downstream targets GLUT1 and LDHA. EIF3F knockdown attenuates VAV2-driven oncogenic phenotypes and tumor progression in xenograft models, validating this axis as a functional dependency. This study uncovers a “signaling-deubiquitination-metabolism” regulatory nexus in ESCC and provides rationale for targeting VAV2-EIF3F interaction to overcome glycolysis-dependent therapy resistance. Graphical