4-aminoquinolines promote redox-dependent ferroptosis sensitization in pancreatic ductal adenocarcinoma cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer marked by oxidative stress, metabolic rewiring, and resistance to cell death. Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, represents a promising therapeutic vulnerability in PDAC; however, intrinsic resistance to ferroptosis limits its therapeutic exploitation. This study shows that 4-aminoquinoline derivatives sensitize PDAC cell lines (MIA PaCa-2 and PANC-1) to erastin-induced ferroptotic cell death. Ferroptosis sensitization occurred independently of caspase-3/7 activation and was associated with increased ROS production, mitochondrial oxidative stress, lipid peroxidation, and redox imbalance. Importantly, sensitivity to ferroptosis was accompanied by decreased GSH levels, reduced intracellular cystine levels, and differential regulation of the KEAP1-Nrf2-p62 axis. While PANC-1 cells exhibited enhanced oxidative stress and KEAP1 upregulation, MIA PaCa-2 cells maintained relative redox homeostasis unless exposed to combined treatment conditions. To our knowledge, this study provides the first evidence that 4- aminoquinoline derivatives promote sensitization to ferroptosis in PDAC and highlights the therapeutic potential of targeting redox metabolism and stress-adaptive signaling to overcome resistance to therapy in pancreatic cancer.