Purpose <p>Early detection and intervention in lung adenocarcinoma (LUAD) are critical for improving patient prognosis. This study explores the role of basic leucine zipper and W2 domains 1 (BZW1, BZAP45) in regulating malignant cellular behavior and glycolytic metabolism in LUAD.</p> Procedures <p>Bioinformatics and clinical information analysis was conducted to study BZW1 expression and its relationship with prognosis, glycolysis-related genes expression and PET/CT parameters of 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in LUAD. BZW1 was knocked out in A549 cell line and verified. <i>In vitro</i> and <i>in vivo</i> studies were performed to analyze BZW1’s impact on malignant behaviors and glycolysis. Non-targeted mass spectrometry analyzed xenograft tumor metabolites and potential biomarkers.</p> Results <p>Bioinformatic analyses identified BZW1 as a pivotal gene driving LUAD progression. The retrospective analysis revealed that BZW1 expression is elevated in LUAD tissues and is significantly correlated with clinical tumor parameters and metabolic parameters obtained from [¹⁸F]FDG PET/CT. <i>In vitro</i> assays demonstrated that BZW1 overexpression promotes LUAD cell proliferation, migration, and invasion. <i>In vivo</i> experiments with mouse xenograft models confirmed that BZW1 promotes tumor growth. Further analysis revealed that BZW1 may facilitate glycolysis and the Warburg effect by upregulating hypoxia inducible factor-1α (HIF-1α) and cellular Myelocytomatosis (c-Myc).</p> Conclusions <p>These findings highlighted the role of BZW1 in LUAD metabolism and may promote tumor progression through modulating of glycolytic pathways. In conclusion, BZW1 is significantly associated with LUAD malignancy and [¹⁸F]FDG PET/CT derived metabolic parameters. It could provide a potential molecular target for the diagnosis and treatment of LUAD, offering new insights into precision oncology.</p>