Enhancing Ferroptosis-Mediated\nRadiosensitization <i>via</i> Synergistic Disulfidptosis\nInduction

Ferroptosis plays an important role in radiotherapy (RT),\nand the\ninduction of ferroptosis can effectively sensitize radiotherapy. However,\nthe therapeutic efficiency is always affected by ferroptosis resistance,\nespecially SLC7A11 (Solute Carrier Family 7 Member 11)-cystine-cysteine-GSH\n(glutathione)-GPX4 (glutathione peroxidase 4) pathway-mediated resistance.\nIn this study, tumor-microenvironment self-activated high-Z element-containing\nnanoferroptosis inducers, PEGylated Fe–Bi–SS metal–organic\nframeworks (FBSP MOFs), were developed to sensitize RT. Unexpectedly,\nferroptosis-resistant SLC7A11 would be self-adaptively upregulated,\nleading to self-responsive ferroptosis resistance. Since the conversion\nfrom SLC7A11-transported cystine to cysteine is highly glucose-dependent,\nglucose oxidase (GOx) was incorporated in the MOFs, causing the depletion\nof NADPH (nicotinamide adenine dinucleotide phosphate) to terminate\nthe conversion from cystine to cysteine, relieving the self-adaptive\nferroptosis resistance. Excitingly, the accumulation of cystine would\nsynergistically lead to disulfide stress and trigger disulfidptosis,\nmaking a new contribution to enhance therapeutic efficiency. Moreover,\nthe hydrogen peroxide produced during glucose oxidation could also\ncascade-react with the Fenton reaction, therefore enhancing ferropotosis.\nBoth <i>in vitro</i> and <i>in vivo</i> results\nsuggested that therapeutic efficiency of ferroptosis-mediated radiosensitization\ncould be enhanced benefiting from synergistic disulfidptosis induction,\nindicating that disulfidptosis might be an efficient strategy to relieve\nferroptosis resistance and enhance RT efficiency.