Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China.
Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300384, China.
J Hazard Mater. 2023 Jan 15;442:130039. doi: 10.1016/j.jhazmat.2022.130039. Epub 2022 Sep 21.
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 environment 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-1β and IL-18. Importantly, 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.
氧化锌纳米粒子（ZnO NPs）已广泛应用于日用品、临床诊断、药物输送和农业生产等领域。ZnO NPs 的不当使用可能会对生态环境和公众健康构成威胁。肝脏已被认为是 ZnO NPs 的关键毒性靶标。然而，ZnO NPs 是否通过细胞焦亡导致肝细胞死亡的问题尚未得到解答，氧化应激对 ZnO NPs 诱导的细胞焦亡的影响仍是一个谜。我们揭示了 ZnO NPs 破坏了锌稳态并诱导了大鼠肝脏的氧化应激损伤。同时，ZnO NPs 在大鼠肝脏和 HepG2 细胞中引发了 NLRP3-ASC-Caspase-1 炎症复合物的组装和细胞焦亡，进一步导致 GSDMD 的激活，促进包括 IL-1β 和 IL-18 在内的炎症细胞因子的漏出。重要的是，抑制氧化应激被发现可以防止暴露于 ZnO NPs 的肝细胞发生细胞焦亡。我们确定了 ZnO NPs 诱导肝损伤的新机制，证明了经典 Caspase-1 依赖性细胞焦亡途径的激活，并阐明了抗氧化应激对细胞焦亡损伤的保护作用。我们的发现为 ZnO NPs 的风险评估和与细胞焦亡相关的临床治疗靶点的探索提供了支持。
