FBXW7 Mutations Reprograms Glucose Metabolism by Activating the ETV6-GLUT Axis in Endometrial Cancer
Endometrial cancer (EC) is associated with metabolic reprogramming, driven in part by mutations in FBXW7, a key tumor suppressor. In this study, we reveal that FBXW7 regulates glucose metabolism by targeting ETV6 for ubiquitination and proteasomal degradation. Loss of FBXW7 leads to ETV6 stabilization, which in turn upregulates GLUT1 expression and promotes its localization to the plasma membrane. This enhances glucose uptake and reprograms cellular metabolism toward increased aerobic glycolysis and oxidative phosphorylation. Functional studies demonstrate that ETV6 overexpression accelerates EC cell proliferation, colony formation, and tumor growth in vitro and in vivo, effects that are significantly attenuated by pharmacological inhibition or genetic knockdown of GLUT1. Mechanistically, ETV6 directly binds to the GLUT1 promoter via its ETS and PNT domains, driving its transcriptional activation. Furthermore, metabolomics analyses reveal alterations in glycolytic and TCA cycle intermediates, highlighting the broad impact of the FBXW7-ETV6-GLUT1 axis on metabolic pathways. These findings establish ETV6 as a central mediator of FBXW7-deficiency-driven metabolic reprogramming and tumor progression in EC. Targeting GLUT1 provides a potential therapeutic strategy to mitigate ETV6-induced tumor growth and metabolic remodeling in endometrial cancer. Overall design: RNA seq of  Human Ishikawa Cells in control and experiment ETV6 overexpress group