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The present study aimed to investigate the hepatotoxicity mechanism of ZnO NPs and traditional non-nano ZnO particles, both in vivo and in vitro, and identify the differences in their toxic effects. The results showed that the extent and conditions of zinc ion release from ZnO NPs were inconsistent with those of ZnO. The RNA-seq results revealed that the expression quantity of differentially expressed genes (DEGs) and differentially expressed transcripts (DETs) affected by ZnO NPs was more than in ZnO, and the overall differences in genes or transcripts in the ZnO NPs group were more pronounced than in the ZnO group. Furthermore, the cell inactivation, oxidative stress, mitochondrial damage, and intracellular calcium overload induced by ZnO NPs were more serious than ZnO in HepG2 cells. Moreover, compared with traditional ZnO, the rat liver damage induced by ZnO NPs was more significant, with evidence of higher AST and ALT levels, weaker antioxidant capacity, and more serious histopathological damage (p &lt; 0.05). In summary, the hepatotoxicity of ZnO NPs was more serious than that of conventional ZnO, which is helpful to understand the hepatotoxicity mechanism of Zn compounds in different states and improve the risk assessment of novel nano ZnO products in a variety of applications.<\/jats:p>","DOI":"10.3390\/ijms23126724","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T01:48:12Z","timestamp":1655430492000},"page":"6724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Lethality of Zinc Oxide Nanoparticles Surpasses Conventional Zinc Oxide via Oxidative Stress, Mitochondrial Damage and Calcium Overload: A Comparative Hepatotoxicity Study"],"prefix":"10.3390","volume":"23","author":[{"given":"Xingyao","family":"Pei","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-0719","authenticated-orcid":false,"given":"Haiyang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Xu","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Department of Animal Pharmacy, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300384, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cun","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Department of Animal Pharmacy, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300384, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1542-997X","authenticated-orcid":false,"given":"Daowen","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Department of Animal Pharmacy, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300384, China"},{"name":"Tianjin Key Laboratory of Biological Feed Additive Enterprise, S&E Burgeoning Biotechnology (Tianjin) Co., Ltd., Tianjin 300383, China"},{"name":"State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, College of Pharmacy, Nankai University, Haihe Education Park, Tongyan Road No.38, Tianjin 300353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusheng","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s11671-018-2532-3","article-title":"Properties of Zinc Oxide Nanoparticles and Their Activity Against Microbes","volume":"13","author":"Siddiqi","year":"2018","journal-title":"Nanoscale Res. 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