Ferroptosis-Based Nanotherapy for Pancreatic Ductal Adenocarcinoma Through Glutathione Depletion and Iron Accumulation

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis and remains highly refractory to standard chemotherapy owing to its unique tumor microenvironment (TME) and metabolic reprogramming. A defining feature of PDAC is that the near-ubiquitous presence of oncogenic KRAS mutations, together with NRF2 activation, generates abnormally high levels of reactive oxygen species (ROS) and renders the cells strongly dependent on an amplified glutathione (GSH)-based antioxidant program (the SLC7A11–GSH–GPx4 axis) for survival. This single metabolic axis simultaneously neutralizes drug-induced ROS to sustain chemoresistance and, through GPx4-mediated detoxification of lipid peroxides, suppresses ferroptosis—an iron-dependent, apoptosis-independent form of cell death. Because ferroptosis does not rely on the apoptotic or immune machinery that PDAC readily evades, its induction directly exploits this redox-metabolic vulnerability, distinguishing the GSH–GPx4 and iron-metabolism axes from conventional immune- or DNA-damage-based targets. This review analyzes the regulatory mechanisms of GSH homeostasis linked to treatment resistance in PDAC and discusses nanoparticle therapeutics rationally designed around the two central ferroptosis pathways: the GSH–GPx4 axis and the iron-metabolism axis.