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.

纳米材料（NMs）的暴露是对人类健康的新威胁，因此迫切需要了解它们的细胞内行为和相关的毒性作用。Ferroptosis是新发现的铁介导的细胞死亡，与细胞凋亡或其他细胞死亡途径不同。当前尚无证据表明“无铁”改造的NMs对肥大症的作用。我们通过几种方法表明：（1）氧化锌纳米颗粒（ZnO NPs）诱导的细胞死亡涉及肥大症；（2）ZnO NPs引发的肥大病与活性氧（ROS）和脂质过氧化的升高，谷胱甘肽（GSH）的消耗和谷胱甘肽过氧化物酶4（GPx4）的下调有关；（3）ZnO NPs通过协调铁的吸收，储存和输出来破坏细胞内的铁稳态。（4）p53主要参与ZnO NPs引起的肥大作用。（5）ZnO颗粒残留物和溶解的锌离子均促成铁锈病。总之，我们的数据为受精卵诱导的一种新的细胞死亡表型提供了新的机制。