Dihydrofolate Reductase (DHFR) Inhibition Promotes Ferroptotic Cell Death Through Nrf2 Suppression to Enhance Radiosensitivity In Pancreatic Ductal Adenocarcinoma (PDAC) Cells

Abstract Pancreatic cancer is one of the most aggressive and fatal malignancies of the digestive system. Radiotherapy plays an important role for local control of locally advanced, unresectable pancreatic cancer (LAPC). Given that the application of radiotherapy is restricted by radiation resistance of pancreatic cancer, radiosensitizers hold promise to overcome pancreatic ductal adenocarcinoma (PDAC) radioresistance and improve patient outcomes. Our research demonstrated that high dihydrofolate reductase (DHFR) expression correlates with poorer survival in pancreatic cancer, associated with transcriptional reprograms regulating proliferation and DNA repair. Methotrexate, an inhibitor of DHFR, sensitizes PDAC cell lines to ionizing radiation, reducing clonogenicity and proliferation, and synergistically triggering robust ferroptotic cell death via Nrf2 pathway inhibition. Our findings unveil a novel therapeutic perspective leveraging synergistic oxidative damage and deregulated metabolism to confront radioresistance in PDAC.