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In recent decades, a range of toxicological effects were highlighted on hepatotoxic risk during ZnO\u2010NPs exposure without precise mechanistic verification. The current study employed proteomic profiling (LC\u2010MS\/MS) to unveil the interaction of ZnO\u2010NPs with human serum proteins (protein corona) and its relevant hepatotoxic mechanisms. Further, chicken embryo model and primary hepatocyte cell culture protocols (fluorescence assays and confocal imaging) were used to explore developmental hepatotoxicity and cellular stress responses respectively. Further, mediatory role of redox enzymes by siRNA experiments and synergistic effect of ZnO\u2010NPs on cellular impact of disease risk factors were also explored. The protein corona composition provides plausible mechanistic insights on liver transport and associated hepatotoxic pathways (Reactome and KEGG). Moreover, the detrimental impact on developing embryonic liver, RBC and tissue redox enzymes were also observed. The expression studies (RT\u2010qPCR and western blot) indicate an elevated response of oxidative stress associated genes (HO\u20101 and NQO1) and cellular stress signaling factors (HSP27, JNK, P53, c\u2010JUN, MAPK). The current study revealed a stimulatory effect of ZnO\u2010NPs on oxidative stress, cellular calcium overload and autophagy. Further, the mediatory effect of NOX2 and XO on ZnO\u2010NPs induced cytotoxicity and superoxide generation was validated. Notably, ZnO\u2010NPs exposure increased the adverse effect of inflammatory and metabolic risk factors in hepatocytes. Overall results highlight novel mechanistic insights on hepatotoxic effect of ZnO\u2010NPs towards a precise assessment on the magnitude of human exposure risk.<\/jats:p>","DOI":"10.1002\/jbt.70480","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T11:43:13Z","timestamp":1756813393000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ZnO Nanoparticles Interacts With Unique Serum Proteins and Induce Stress Signaling During Hepatoxicity \u2010 A Proteomics and Molecular Pathways Study"],"prefix":"10.1002","volume":"39","author":[{"given":"Gobichettipalayam Balasubramaniam","family":"Maadurshni","sequence":"first","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balamurali","family":"Mahalakshmi","sequence":"additional","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manikandan","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"},{"name":"Dalton Cardiovascular Research Center University of Missouri Columbia Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panchatcharam","family":"Swathika","sequence":"additional","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ganesan","family":"Harinikkamatchi","sequence":"additional","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anand Kumar","family":"Anusha","sequence":"additional","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-0155","authenticated-orcid":false,"given":"Jeganathan","family":"Manivannan","sequence":"additional","affiliation":[{"name":"Environmental Health and Toxicology Laboratory, Department of Environmental Sciences School of Life Sciences, Bharathiar University Coimbatore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/1062562"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/925494"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","unstructured":"J.Liu Y.Kang S.Yin et al. 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