4.8 Article

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

Journal

SMALL
Volume 19, Issue 24, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/smll.202208063

Keywords

ferritin; ferritinophagy; ferroptosis; MoS2 nanosheets; NCOA4

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This study reveals that MoS2 nanosheets induce ferroptosis in vivo and in vitro, which is caused by the nanosheet themselves rather than by the dissolved ions. MoS2 nanosheets enter the cells through macropinocytosis and localize to the lysosome, causing an increase in lysosomal membrane permeability. This leads to the activation of NCOA4-dependent ferritinophagy and the inhibition of FPN, resulting in the leakage of Fe2+ into the cytoplasm and ultimately ferroptosis. The inhibition of FPN further aggravates the overload of Fe2+ in the cell.
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.

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