Cysteine Depletion-Initiated Redox Imbalance Evokes Ferroptosis and Pyroptosis for Enhanced Pancreatic Cancer Therapy
Hao Chen, Binbin Ding, Pan Zheng, Bin Liu, Jia Tan, Qi Meng, Jing Li, Meifang Wang, Ping’an Ma, Jun Lin
Abstract
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 ( PVP CuO NPs) are proposed first for inducing redox imbalance initiated by cysteine (Cys) depletion. The PVP CuO NPs not only deplete cysteine and produce H 2 O 2 but also exhibit peroxidase (POD)-like activity, efficiently converting H 2 O 2 into hydroxyl radicals ( • OH). 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 Cu 2+ ions generation further initiate pyroptosis, achieving Cys targeted high-efficiency pancreatic cancer therapy.