GFPT1 drives esophageal cancer progression by inhibiting ER stress-mediated excessive autophagy

GFPT1, the rate-limiting enzyme of the hexosamine biosynthesis pathway, promotes various cancers but its role in esophageal cancer is unclear. GFPT1 expression was assessed by public datasets, western blotting, and IHC. GFPT1-silenced cells were established via siRNA. Proliferation, migration, invasion, apoptosis, ER stress, and autophagy markers were evaluated by CCK-8, colony formation, Transwell, wound healing, flow cytometry, western blotting, and LC3 immunofluorescence. In addition, rescue experiments were performed using the ER stress inhibitor 4-PBA in GFPT1-knockdown cells, and O-GlcNAcylation levels were examined by western blot. GFPT1 was highly expressed in esophageal cancer tissues. Knockdown of GFPT1 suppressed proliferation, invasion, and migration, while enhancing apoptosis. GFPT1 depletion upregulated ER stress markers (GRP78, GRP94, p-PERK, p-eIF2α) and autophagy-related changes (increased LC3-II/LC3-I ratio, ATG5, ATG7, and reduced p62), and reduced overall O-GlcNAcylation. Importantly, treatment with 4-PBA significantly reversed the GFPT1 knockdown-induced suppression of proliferation, migration, and invasion, and rescued the alterations in ER stress markers, indicating that the phenotypic effects are causally mediated, at least in part, through the ER stress pathway. GFPT1 knockdown impedes esophageal cancer progression by reducing aggressive phenotypes and promoting apoptosis, potentially via ER stress and autophagy activation.