The palmitoylation enzyme ZDHHC2 promotes esophageal cancer progression via N-acetylaspartylglutamate.

Esophageal cancer is a highly lethal malignancy of the digestive system, and its underlying molecular mechanisms remain incompletely understood. Protein palmitoylation, a critical lipid-based post-translational modification, has recently emerged as a key regulatory process implicated in various cancers. ZDHHC2, a prominent member of the palmitoyltransferase family, exhibits aberrant expression and functional dysregulation across multiple tumor types, suggesting its potential involvement in esophageal carcinogenesis. In this study, we utilized data from genome-wide association studies (GWAS) and applied a two-sample Mendelian randomization approach to systematically evaluate the causal relationship between ZDHHC2 and esophageal cancer. Moreover, we explored the indirect mediating role of metabolites in this association. Our analysis revealed a significant positive correlation between elevated ZDHHC2 expression and increased risk of esophageal cancer (OR = 1.178, P = 0.031). Notably, the metabolite N-acetylaspartylglutamate (NAAG) was identified as a partial mediator in this relationship, accounting for 6.1% of the total effect (P = 0.038). As a key derivative in glutamate metabolism, NAAG is implicated in tumor metabolism, immune suppression, and signal transduction. These findings suggest that the ZDHHC2–NAAG axis may represent a critical mechanism underlying metabolic reprogramming and immune evasion in esophageal cancer, providing new insights into its pathogenesis and potential therapeutic targets.