Abstract
Exposure to nanomaterials (NMs) is an emerging threat to human health, and the understanding of their intracellular behavior and related toxic effects is urgently needed. Ferroptosis is a newly discovered, iron-mediated cell death that is distinctive from apoptosis or other cell-death pathways. No evidence currently exists for the effect of “iron free” engineered NMs on ferroptosis. We showed by several approaches that (1) zinc oxide nanoparticles (ZnO NPs)-induced cell death involves ferroptosis; (2) ZnO NPs-triggered ferroptosis is associated with elevation of reactive oxygen species (ROS) and lipid peroxidation, along with depletion of glutathione (GSH) and downregulation of glutathione peroxidase 4 (GPx4); (3) ZnO NPs disrupt intracellular iron homeostasis by orchestrating iron uptake, storage and export; (4) p53 largely participates in ZnO NPs-induced ferroptosis; and (5) ZnO particle remnants and dissolved zinc ion both contribute to ferroptosis. In conclusion, our data provide a new mechanistic rationale for ferroptosis as a novel cell-death phenotype induced by engineered NMs.
Highlights
Nanomaterials (NMs) readily enter the human body through respiratory inhalation, oral ingestion or a dermal route, cross the plasma membrane and reach the inside of cells, triggering cell death[1]
zinc oxide nanoparticles (ZnO NPs) characterized by X-ray diffraction (XRD) with CuKα radiation revealed a crystalline nature structure which is consistent with the standard zincite, JCPDS 50664 (Supplementary Fig. 2)
Previous in vitro and in vivo studies demonstrated the association of ZnO NPs exposure with various cell-death pathways; whether ZnO NPs, along with other “iron free” NMs induce ferroptosis has not been reported
Summary
Nanomaterials (NMs) readily enter the human body through respiratory inhalation, oral ingestion or a dermal route, cross the plasma membrane and reach the inside of cells, triggering cell death[1]. The disruption of cell-death homeostasis is associated with various diseases, including neurodegenerative diseases, immune disorders, diabetes and cancers. Thereafter, it is important to elaborate the molecular processes of NMs-regulated cell death[2,3]. The majority of cell-death modalities are associated with NMs-induced cytotoxicities. Ferroptosis is a recently recognized cell death with unique morphological, genetic and biochemical characteristics that are distinct from apoptosis, autophagy or necrosis[4,5]. Ferroptosis is an iron-dependent accumulation of lipid reactive oxygen species (ROS) process. Small molecule inducers or inhibitors of ferroptosis through targeting iron metabolism or lipid peroxidation have been extensively studied[6]
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