Abstract

Lung adenocarcinoma, the predominant type of non-small cell lung cancer, is associated with poor survival outcomes due to late-stage diagnosis, resistance to therapy, and lack of effective metabolic-targeted strategies. Increased glycolysis is a hallmark of LUAD progression, yet the upstream transcriptional and post-translational regulators of glycolytic enzymes remain incompletely defined. This study aims to clarify the molecular mechanisms through which transcription factors and ubiquitin ligases coordinate glycolytic activation and tumor progression in LUAD. We identified ZBTB7B as a transcriptional activator of the non-canonical glycolytic enzyme ADPGK. ZBTB7B expression was significantly increased in LUAD tissues and cell lines, associated with poor prognosis, and enhanced proliferation, migration, and glycolytic flux in an ADPGK-dependent manner. Mechanistically, the E3 ubiquitin ligase NEDD4 directly interacted with ZBTB7B, mediating its ubiquitination at K450 and proteasomal degradation, thereby suppressing ADPGK expression and glycolysis. NEDD4 overexpression suppressed LUAD growth both in vitro and in vivo, effects that were reversed by ZBTB7B restoration. Collectively, this work reveals a novel NEDD4/ZBTB7B/ ADPGK axis that integrates transcriptional and post-translational regulation of glycolysis, offering potential therapeutic targets for metabolic intervention in LUAD.