Abstract

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.

摘要

Ferroptosis是多不饱和脂肪酸过度过氧化引起的铁依赖性细胞死亡。它可以被铁基纳米颗粒激活，作为潜在的癌症治疗靶标。然而，铁基纳米颗粒的细胞内转化仍然是模棱两可的，随后的促肥大作用机制也不清楚。在这里，我们通过使用X射线吸收近边缘结构光谱学确定了细胞中超小型超顺磁性氧化铁纳米颗粒（USPIO）的时程代谢。而且，从暴露于USPIO的细胞获得的整合的定量转录组和蛋白质组数据显示出铁锈病的标志性特征。随着氧化铁的化学物质转化为铁蛋白，细胞内GPX4的表达下调，脂质过氧化物开始积累。