Mitochondrially targeted deferasirox kills cancer cells via simultaneous iron deprivation and ferroptosis induction

Iron chelation has been proposed as an anti-cancer approach; however, iron chelators are generally non-specific for cancer cells and rely on the higher sensitivity of malignant cells to iron deprivation and accumulation of the drug in tumor tissue via the enhanced permeability and retention effect. Here, we present mitochondrially targeted deferasirox (mitoDFX), a redox-active iron chelator that deprives cells of biologically active iron, as evidenced by a decrease in [Fe-S] cluster and heme-containing proteins. Notably, mitoDFX also depletes the major cellular antioxidant glutathione and induces lipid peroxidation, both of which are hallmarks of ferroptosis, resulting in selective induction of cell death in cancer cells. In summary, targeting deferasirox into the mitochondria results in an agent that has a unique ability to elicit iron deprivation and produce toxic lipid peroxides via its redox activity, thus harnessing the dual nature of iron in a single molecule to combat cancer. ### Competing Interest Statement The authors have declared no competing interest. Raw proteomics data ( [Fig. 4][1] and S3 ) are provided as Supplementary File 2 . [1]: #F4