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<p>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.</p> Graphical Abstract <p></p>

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VAV2 drives glycolytic reprogramming in esophageal squamous cell carcinoma via EIF3F-mediated MTA1 deubiquitination

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月9日

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  • Weiling Liu,
  • Yangyang Hou,
  • Bo Wang,
  • Fengna Liu,
  • Lu Zheng,
  • Hailing Wang,
  • Shaomei Li,
  • Xiaowan Zhou,
  • Mengting Zhang,
  • Shujun Yang,
  • Yan Zhao

摘要

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 Abstract