Gamma-glutamyl transferase as a redox-gatekeeper biomarker for pancreatic cystic neoplasms: A concise roadmap from epidemiology to bedside

Serum gamma-glutamyl transferase (GGT), a marker of hepatobiliary and oxidative stress, emerged as a predictor of incident pancreatic cystic neoplasms (PCNs) in a 2.65-million nationwide cohort followed for > 10 years. The highest GGT quartile conferred 11% excess PCN risk, with hazard ratios rising across quartiles and persisting after 3- and 5-year lag exclusions. In redox-oncology, pancreatic <i>GGT1</i> isoform upregulated by oncogenic <i>KRAS</i> cleaves extracellular glutathione, promoting reactive oxygen species-mediated DNA damage, Wnt/β-catenin, and interleukin-6/signal transducer and activator of transcription 3 inflammatory circuits cooperating with <i>GNAS</i> mutations to initiate intraductal papillary mucinous neoplasm. We propose: (1) Refining age-specific GGT thresholds <i>via</i> repeated measurements and restricted cubic splines; (2) Integrating GGT with carbohydrate antigen 19-9, carcinoembryonic antigen, and <i>KRAS</i>/<i>GNAS</i> circulating tumor DNA in machine-learning radiomic models for personalized 5-year malignancy risks per Fukuoka guidelines; and (3) Validating cost-effectiveness in multi-ethnic populations before screening. This repositions GGT as a globally available redox biosignature for PCN early detection, potentially reducing pancreatic cancer burden.