A chiral fluorescent Ir(iii) complex that targets the GPX4 and ErbB pathways to induce cellular ferroptosis

Ferroptosis has recently emerged as a non-apoptotic form of programmed cell death and promising target for anticancer treatment. However, it is challenging to discover ferroptosis inducers with both highly selective tumour targeting and low cytotoxicity to normal cells. Here, we report an Ir(iii) complex, Ir1, that contains a novel chiral pyridine RAS-selective lethal ligand (Py-RSL). This complex effectively inhibits glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) to induce ferroptosis in human fibrosarcoma (HT-1080) cells. Notably, metal coordination not only endows Ir1 with fluorescent properties for convenient cellular real-time tracking but also efficiently reduces the off-target toxicity of the Py-RSL ligand. Furthermore, label-free quantitative proteomic profiling revealed that Ir1 simultaneously inhibits the ErbB signalling pathway to enhance tumour suppression. Our work is the first to report a ferroptosis-inducing iridium complex with dual mechanisms of inhibition and provides a highly selective and efficient route to develop new ferroptosis-inducing metallodrugs.