Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis

Triple-negative breast cancer (TNBC) is an aggressive malignancy, with limited targeted treatment options. In this study, we developed a novel triphenylphosphine (TPP)-modified deferasirox (DFX) titanium complex (<b>Ti-DFX-TPP</b>) to disrupt iron homeostasis in TNBC cells through transmetalation. <b>Ti-DFX-TPP</b> depletes the labile iron pool, triggering a compensatory upregulation of transferrin receptor 1 (TfR1) in response to an intracellular iron deficiency. The disruption of iron metabolism by <b>Ti-DFX-TPP</b> increases reactive oxygen species (ROS) levels, which in turn lead to mitochondrial dysfunction and DNA damage, ultimately inhibiting cancer cell growth. In vivo studies further demonstrated that <b>Ti-DFX-TPP</b> inhibits tumor growth without significant toxicity to major organs. These findings suggest that <b>Ti-DFX-TPP</b> is a promising therapeutic candidate for TNBC, as it exploits the disruption of iron metabolism and ROS pathways to enhance its anticancer efficacy.