2D MoS2Nanosheets Induce Ferroptosis by Promoting NCOA4‐Dependent Ferritinophagy and Inhibiting Ferroportin

Abstract The exposure of MoS 2 nanosheets can cause cytotoxicity, which causes health risks and affects its medical applications. However, knowledge of the underlying molecular mechanisms remains limited. This study reports that MoS 2 nanosheets induces ferroptosis in vivo and in vitro, which is caused by the nanosheet themselves rather than by the dissolved ions. MoS 2 nanosheets induce ferroptosis in epithelial (BEAS‐2B) and macrophage (RAW264.7) cells due to nuclear receptor coactivator 4 (NCOA4)‐dependent excusive ferritinophagy and the inhibition of ferroportin‐1 (FPN). In this process, most of the MoS 2 nanosheets enter the cells via macropinocytosis and are localized to the lysosome, contributing to an increase in the lysosomal membrane permeability. At the same time, NCOA4‐dependent ferritinophagy is activated, and ferritin is degraded in the lysosome, which generates Fe 2+ .Fe 2+ leaks into the cytoplasm, leading to ferroptosis. Furthermore, the inhibition of FPN further aggravates the overload of Fe 2+ in the cell. It has also been observed that ferroptosis is increased in lung tissue in mouse models exposed to MoS 2 nanosheets. This work highlights a novel mechanism by which MoS 2 nanosheets induce ferroptosis by promoting NCOA4‐dependent ferritinophagy and inhibiting FPN, which could be of importance to elucidate the toxicity and identify the medical applications of 2D nanoparticles.