Peroxiredoxin Depletion and Oxidative Stress by Cyclometalated Ir(III)-Isatin Complexes Renders Ferroptosis and Autophagic Cell Death in Triple-Negative Breast Cancer

The ability to induce nonapoptotic cell death is critical to fight apoptosis-resistant cancers. Excessive reactive oxygen species (ROS) can promote nonapoptotic cell death. We report six potent cyclometalated iridium(III) complexes derived from isatin-hydrazone Schiff bases with nanomolar IC50 values against pancreatic (MIA-PaCa-2, PANC-1) and breast (MDA-MB-231, MCF-7) cancer cells. These metal-based anticancer agents promote excess ROS accumulation, triggering ferroptosis and autophagy. The lead Ir(III) complex (1), bearing an imidazole-isatin ligand, shows high aqueous stability, maximum cellular uptake, and the strongest cytotoxicity. Proteomic analysis reveals upregulation of S100-A8, RAB27A, and Galectin-1 as an adaptive mechanism to regulate ROS. However, excessive ROS production surpasses the capacity of cellular antioxidant defenses, downregulating ROS-controlling proteins such as peroxiredoxins (Prx) and superoxide dismutase (SOD) accompanied by overexpression of heme oxygenase contributing to lipid peroxidation. Additionally, the complexes reduce inflammation by suppressing MIF and TGF-β signaling. Low systemic toxicity and antiangiogenic activity in zebrafish further support their therapeutic potential.