Cysteine Depletion-Initiated Redox Imbalance Evokes Ferroptosis and Pyroptosis for Enhanced Pancreatic Cancer Therapy

Highly proliferative and reactive oxygen species (ROS) overexpression make pancreatic cancer upregulate cysteine (Cys) uptake to maintain redox homeostasis, which indicates that Cys may be a potential target for the treatment of pancreatic cancer. Herein, polyvinylpyrrolidone (PVP) modified CuO nanoparticles ((CuO)-Cu-PVP NPs) are proposed first for inducing redox imbalance initiated by cysteine (Cys) depletion. The (CuO)-Cu-PVP NPs not only deplete cysteine and produce H2O2 but also exhibit peroxidase (POD)-like activity, efficiently converting H2O2 into hydroxyl radicals ((OH)-O-center dot). Simultaneously, Cys depletion also induces nicotinamide adenine dinucleotide phosphate (NADPH) consumption and thioredoxin (TXN) synthesis to trigger ferroptosis. Then the remarkable redox imbalance together with a mass of Cu2+ ions generation further initiate pyroptosis, achieving Cys targeted high-efficiency pancreatic cancer therapy.