A hypoxia–lactate metabolism-related gene signature for prognostic stratification in pancreatic adenocarcinoma

Pancreatic cancer (PC) is marked by a unique tumor microenvironment driven by chronic hypoxia and dysregulated lactate metabolism, but the combined prognostic utility of these factors remains unclear. Via integrated transcriptomic analysis of the TCGA-PAAD and GSE183795 datasets, we identified a six-gene signature ( FHL2 , ITGA3 , KCNJ3 , KLF5 , MSLN , and S100A16 ) using weighted gene co-expression network, least absolute shrinkage and selection operator, and Cox regression analyses. This signature effectively stratified patients into high- and low-risk groups with significantly different overall survival ( p < 0.0001). High-risk tumors exhibited an immunosuppressive microenvironment, an increased abundance of M0 macrophages, an elevated tumor mutational burden, and hypothesis-generating evidence of greater sensitivity to Hsp90 inhibitors. Mechanistic exploration suggested a hypothetical lncRNA–miRNA regulatory axis that warrants further experimental verification. This hypoxia–lactate metabolism-related signature offers a robust tool for prognostic stratification and generates therapeutic hypotheses that merit further preclinical and clinical investigation.