Zinc oxide nanoparticles (ZnO NPs) are one of the most commonly used metal oxide particles in many industrial fields. Many studies have shown that ZnO NPs induce harmful effects to human skin, but the mechanisms remain poorly understood. Our results showed that ZnO NPs concentration-dependently induced cytotoxicity, ROS accumulation, and mitochondrial dysfunction in HaCaT cells. The expressions of adaptive antioxidant response transcriptional factor NRF2 and autophagy-related proteins P62 and LC3 II/I were increased by ZnO NPs. Knock-down of NRF2 (NRF2-KD) sensitized the cells to ZnO NPs-induced autophagy and cytotoxicity while an autophagy inhibitor, 3-methyladenine, protected the cells from ZnO NPs-induced cell death. These results demonstrated that NRF2 deficiency sensitizes human keratinocytes to ZnO NPs induced autophagy and cytotoxicity, and proposed a key role of NRF2 in protecting skin cells against ZnO NPs through regulation of antioxidants and autophagy.

氧化锌纳米颗粒（ZnO NPs）是许多工业领域中最常用的金属氧化物颗粒之一。许多研究表明，ZnO NPs 会对人体皮肤产生有害影响，但其机制仍知之甚少。我们的结果表明，ZnO NPs 浓度依赖性地诱导 HaCaT 细胞的细胞毒性、ROS 积累和线粒体功能障碍。ZnO NPs 增加了适应性抗氧化反应转录因子 NRF2 和自噬相关蛋白 P62 和 LC3 II/I 的表达。击倒 NRF2 ( NRF2-KD) 使细胞对 ZnO NPs 诱导的自噬和细胞毒性敏感，而自噬抑制剂 3-甲基腺嘌呤保护细胞免受 ZnO NPs 诱导的细胞死亡。这些结果表明，NRF2 缺乏使人角质形成细胞对 ZnO NPs 诱导的自噬和细胞毒性敏感，并提出 NRF2 在通过调节抗氧化剂和自噬保护皮肤细胞免受 ZnO NPs 的关键作用。