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）已广泛应用于日常生活用品、临床诊断、药物输送和农业生产等领域。ZnO NPs的不当使用可能对生态环境和公众健康构成风险。肝脏被认为是 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然是一个谜。我们发现 ZnO NPs 破坏了大鼠肝脏的锌稳态并诱导了氧化应激损伤。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，进一步引起GSDMD的激活，促进包括IL-1β和IL-18在内的炎性细胞因子的泄漏。重要的是，发现抑制氧化应激可以防止暴露于 ZnO NPs 的肝细胞发生焦亡。我们确定了一种由 ZnO NPs 诱导的肝损伤的新机制，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 的风险评估和焦亡相关临床治疗的靶点探索提供了支持。