Time-course effect of ultrasmall superparamagnetic iron oxide nanoparticles on intracellular iron metabolism and ferroptosis activation

Ferroptosis is an iron-dependent cell death caused by excessive peroxidation of polyunsaturated fatty acids. It can be activated by iron-based nanoparticles as a potential cancer therapeutic target. However, the intracellular transformation of iron-based nanoparticles is still ambiguous and the subsequent ferroptosis mechanism is also obscure. Here, we identified the time-course metabolism of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) in cells by using X-ray absorption near edge structure spectroscopy. Also, the integrated quantitative transcriptome and proteome data obtained from the cells exposed to USPIO exhibited hallmark features of ferroptosis. With the chemical species of iron oxide transforming to ferritin, the intracellular GPX4 down-regulated, and lipid peroxide began to accumulate. These results provide evidence that the intracellular metabolism of USPIO induced ferroptosis in a time-dependent manner, and iron over-loaded in cytoplasm along with lipid peroxidation of the membrane are involved in the detailed mechanism of ferroptosis signaling activation.