Fu et al. reveal that hyperactive Nrf2 not only drives GSH metabolism but also upregulates glycolytic, PPP, and NADPH-synthesis genes in mouse esophagus, with Nrf2 ablation, PKM2 ablation, and glycolytic inhibitors suppressing human ESCC proliferation in vitro. This evidence concerns the gene NFE2L2 and esophageal squamous cell carcinoma.