GFPT2 upregulation predicts poor prognosis and is associated with TGF-β/Smad activation in lung adenocarcinoma

BACKGROUND: Glutamine-fructose-6-phosphate amidotransferase 2 (GFPT2) is a rate-limiting enzyme of the hexosamine biosynthetic pathway, but its protein-level expression and functional relevance in lung adenocarcinoma (LUAD) remain unclear. METHODS: GFPT2 protein abundance was evaluated in Clinical Proteomic Tumor Analysis Consortium (CPTAC) LUAD proteomics and validated by Western blotting in paired LUAD and adjacent tissues. The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) transcriptomes were analyzed for differential expression and pathway enrichment, with survival assessed by Kaplan-Meier and Cox regression. Stable GFPT2 knockdown/overexpression in A549 cells was used to examine proliferation, migration, invasion, and transforming growth factor-β (TGF-β)/Smad2/3 signaling by Western blotting. RESULTS: GFPT2 protein was significantly upregulated in LUAD compared with adjacent tissues. TCGA-based analyses showed distinct transcriptional profiles between GFPT2 mRNA-high and GFPT2-low tumors, with enrichment of extracellular matrix organization, cell adhesion, and TGF-β-related signaling. High GFPT2 mRNA expression was associated with poorer overall survival and remained an independent adverse prognostic factor in multivariable Cox models. In A549 cells, GFPT2 overexpression was accompanied by enhanced proliferation, migration, and invasion, whereas GFPT2 knockdown showed the opposite effects. Consistently, GFPT2 upregulation was associated with increased TGF-β1 levels and Smad2/3 phosphorylation, suggesting a positive association with TGF-β/Smad signaling activity. CONCLUSION: GFPT2 is upregulated at the protein level in LUAD and is associates with aggressive cellular phenotypes and unfavorable prognosis. Integrated multi-omics analyses and cell-based experiments support a link between GFPT2 and TGF-β/Smad2/3 pathway activation, indicating GFPT2 as a potential prognostic biomarker and therapeutic target.