Zirconia nanoparticles (ZrO2-NPs) have been increasingly used in industrial, biomedical and dental materials. Nevertheless, the scientific basis for the toxicological effects of ZrO2-NPs is poorly elucidated, and the understanding of the underlying mechanism is still limited. The hepatic biodistribution and toxicologicale ffects of ZrO2-NPs after a single intravenous administration (20 mg/kg bw) in vivo and the toxicological mechanism toward hepatocytes in vitro were investigated. The liver showed continuous ZrO2-NP accumulation over a 28-d period. Moreover, ZrO2-NPs induced steatosis, functional injury, inflammatory response, and gene alternations in the liver. The main gene altered pathways induced by ZrO2-NP exposure were involved in metabolism, cellular processes, and human diseases. Among these pathways, lipid biosynthesis and metabolism alterations were predominant, and P53 signaling was also identified. Precious gene expression quantification further showed alterations in genes related to lipid biosynthesis and metabolism and cell apoptosis. Meanwhile, the results of the in vitro studies demonstrated ZrO2-NP sinduce oxidative stress, lipid accumulation, cell apoptosis and P53-mediated signaling pathway activation in HepG2 cells. This study proves that ZrO2-NPs have impacts on the liver. There is potential concern over the hepatotoxicity of ZrO2-NPs in biomedical applications and occupational exposure through large-scale production. (C) 2020 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.