Oxidative stress-related canonical pyroptosis pathway, as a target of liver toxicity triggered by zinc oxide nanoparticles
Oxidative stress-related canonical pyroptosis pathway, as a target of liver toxicity triggered by zinc oxide nanoparticles
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DOI：
10.1016/j.jhazmat.2022.130039
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发表时间：
2022-09-24
影响因子：
13.6
通讯作者：
Tang, Shusheng
中科院分区：
文献类型：
--
作者：
Pei, Xingyao;Jiang, Haiyang;Tang, Shusheng
纳米氧化锌在日用品、临床诊断、药物释放和农业生产等领域有着广泛的应用。不适当地使用纳米氧化锌会对生态环境和公众健康构成威胁。肝脏已被认为是氧化锌纳米颗粒的重要毒性靶点。然而，目前关于纳米氧化锌是否通过下垂导致肝细胞死亡的问题尚未得到解答，氧化应激对纳米颗粒引起的下垂的影响仍然是一个谜。我们发现，氧化锌纳米颗粒破坏了大鼠肝脏的锌稳态，并诱导了氧化应激损伤。同时，氧化锌纳米粒在大鼠肝脏和HepG2细胞中均可触发NLRP3-ASC-Caspase-1炎性复合体的组装和下垂，进而激活GSDMD，促进包括IL-1β和IL-18在内的炎性细胞因子的渗漏。重要的是，氧化应激的抑制被发现对暴露于氧化锌纳米颗粒的肝细胞的热下垂有保护作用。我们发现了一种新的氧化锌纳米颗粒致肝损伤的机制，证明了典型的依赖于Caspase-1的焦虑症通路的激活，并阐明了抗氧化对焦虑症损伤的保护作用。我们的发现为氧化锌纳米颗粒的风险评估和临床治疗相关下垂的靶向探索提供了支持。
Zinc oxide nanoparticles (ZnO NPs) have been widely used in the fields of daily necessities, clinical diagnosis, drug delivery and agricultural production. The improper use of ZnO NPs could pose a risk to ecological envi-ronment and public health. Liver has been known as a critical toxic target of ZnO NPs. However, the question whether ZnO NPs lead to hepatocyte death through pyroptosis has not been answered yet, and the effect of oxidative stress on ZnO NPs-induced pyroptosis remains a mystery. We revealed that ZnO NPs disrupted zinc homeostasis and induced oxidative stress impairment in rat liver. Meanwhile, ZnO NPs triggered the assembly of NLRP3-ASC-Caspase-1 inflammatory complex and pyroptosis in both rat liver and HepG2 cells, further causing the activation of GSDMD, promoting the leakage of inflammatory cytokines including IL-1 beta and IL-18. Impor-tantly, the inhibition of oxidative stress was found to provide protection against pyroptosis in hepatocyte exposed to ZnO NPs. We identified a novel mechanism of liver damage induced by ZnO NPs, demonstrating the activation of canonical Caspase-1-dependent pyroptosis pathway and clarifying the protection of antioxidation against pyroptosis damage. Our discovery provided a support for risk assessment of ZnO NPs and target exploration for clinical treatment related to pyroptosis.