ARNTL2 promotes metastatic phenotypes through SERPINE1 transcription in KRAS G12D pancreatic cancer.

Despite the prevalence of the KRAS G12D mutation in approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases and its association with the poorest prognosis among KRAS variants, the downstream transcriptional effectors driving its aggressive metastatic phenotype remain poorly defined. Through integrated bioinformatics and experimental validation, we identified ARNTL2 as a factor associated with KRAS G12D-mutant PDAC. ARNTL2 directly bound to the SERPINE1 promoter to activate its expression, establishing an ARNTL2-SERPINE1 axis that orchestrated epithelial-mesenchymal transition and drove metastasis in vitro and in vivo. Rescue experiments confirmed SERPINE1 as the indispensable downstream mediator. Clinical validation demonstrated that ARNTL2 and SERPINE1 protein levels correlated positively and stratified patients into distinct prognostic subgroups. Furthermore, this axis altered sensitivity to selective KRAS G12D inhibition in vitro. These findings identify an experimentally supported ARNTL2-SERPINE1 transcriptional axis in KRAS G12D-mutant PDAC that warrants further validation in genotype-faithful and clinically relevant models.