Dual functioning Ru(II)/Ir(III) complexes for ferroptosis and apoptosis in triple-negative breast cancer: a proof of concept by glutathione depletion.

Although triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, there is a lack of effective targeted therapies because of the negative expression of the targetable bioreceptors. Fighting TNBC requires innovative solutions beyond conventional treatments. Herein, we introduce novel imidazo-phenanthroline-based Ru(II)/Ir(III) complexes that exhibit a dual function on cancer cells by triggering both apoptosis and ferroptosis. By generating a surge of reactive oxygen species (ROS), depleting crucial antioxidants such as GSH (glutathione) and NADPH (nicotinamide adenine dinucleotide phosphate), and disrupting mitochondrial function, these complexes dismantle tumor defenses from within. Mechanistically, these complexes disrupt the antioxidant defense system of tumor cells, reduce mitochondrial membrane potential (MMP), activate caspase, induce lipid peroxidation (LPO) accumulation, cause mitochondrial shrinkage, and downregulate glutathione peroxidase 4 (GPX4), ultimately leading to cancer cell death.