REG4 serves as a prognostic biomarker for pancreatic cancer with long-standing diabetes mellitus by modulating chemoresistance

Background Pancreatic ductal adenocarcinoma (PDAC) in patients with diabetes mellitus (DM) represents a clinically heterogeneous subgroup, yet biomarkers that reflect diabetes-associated tumor biology and chemotherapy response remain limited. In particular, the influence of diabetes duration on treatment resistance in PDAC is poorly understood. Methods We performed an integrated translational analysis combining reanalysis of public single-cell RNA sequencing (scRNA-seq) datasets, clinical serum biomarker profiling, and functional validation using pancreatic cancer cell lines and patient-derived organoids. Circulating REG4 concentrations were measured in independent PDAC cohorts and correlated with diabetes duration, overall survival, and response to FOLFIRINOX. Functional relevance was assessed under diabetes-mimicking hyperglycemic conditions. Results Single-cell transcriptomic analysis demonstrated enrichment of REG4-expressing tumor cells within the classical PDAC subtype specifically in diabetic patients. Clinically, circulating REG4 concentrations were significantly elevated in PDAC patients with long-standing diabetes, and high REG4 levels were associated with poor overall survival and resistance to FOLFIRINOX exclusively in this subgroup. In contrast, no prognostic association was observed in non-diabetic or new-onset diabetic patients. In patient-derived organoids and pancreatic cancer cell lines, chronic glucose exposure induced REG4 expression, activation of WNT/β-catenin signaling, suppression of apoptotic pathways, and increased resistance to FOLFIRINOX, recapitulating key clinical features of long-standing diabetes-associated PDAC. Conclusions These findings suggest REG4 as a candidate diabetes duration–dependent prognostic and predictive biomarker in pancreatic cancer, warranting validation in larger prospective cohorts. By linking metabolic context to chemotherapy resistance through REG4-associated signaling, this study provides a translational framework for patient stratification and treatment optimization in diabetes-associated PDAC.