2D MoS₂ Nanosheets Induce Ferroptosis by Promoting NCOA4-Dependent Ferritinophagy and Inhibiting Ferroportin

The exposure of MoS₂ 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 MoS₂ nanosheets induces ferroptosis in vivo and in vitro, which is caused by the nanosheet themselves rather than by the dissolved ions. MoS₂ 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 MoS₂ 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 Fe²⁺.Fe²⁺ leaks into the cytoplasm, leading to ferroptosis. Furthermore, the inhibition of FPN further aggravates the overload of Fe²⁺ in the cell. It has also been observed that ferroptosis is increased in lung tissue in mouse models exposed to MoS₂ nanosheets. This work highlights a novel mechanism by which MoS₂ 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.