{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:07:51Z","timestamp":1789646871607,"version":"4.0.0"},"reference-count":73,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 Research and Innovation Programme","award":["963845 (ONTOX)"],"award-info":[{"award-number":["963845 (ONTOX)"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Programme","award":["965406 (PrecisionTox)"],"award-info":[{"award-number":["965406 (PrecisionTox)"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Programme","award":["964537 (RISK-HUNT3R)"],"award-info":[{"award-number":["964537 (RISK-HUNT3R)"]}]},{"name":"EU project PARC","award":["101102316"],"award-info":[{"award-number":["101102316"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Steatosis, characterized by excessive fat accumulation in the liver, is a significant precursor to chronic liver disease and hepatocarcinoma. This condition is influenced by multiple contributing factors such as obesity, alcohol consumption, and exposure to chemicals or drugs. Systems biology approaches including transcriptomics and metabolomics can aid in grouping chemicals according to their mode of action. In this study, we analyze transcriptomic and metabolomic data from primary human and transformed hepatocytes, respectively, to differentiate between steatotic and non-steatotic chemicals. Rather than assessing each steatotic compound individually, we pooled several steatotic chemicals in order to minimize compound-specific noise and better identify features associated with the underlying process of steatosis. Differential gene expression analysis revealed established mechanisms involved in steatosis, consistent with the recently updated adverse outcome pathway. Likewise, metabolomic data enabled clear discrimination between steatotic and non-steatotic chemicals. These findings highlight the potential of omics technologies to support chemical grouping based on insights into the molecular mechanisms that drive steatosis development.<\/jats:p>","DOI":"10.3390\/ijms27093825","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discrimination of Steatotic and Non-Steatotic Chemicals Through Transcriptome Analysis in Primary Human Hepatocytes"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5409-8582","authenticated-orcid":false,"given":"Christina A.","family":"Cramer von Clausbruch","sequence":"first","affiliation":[{"name":"Institute of Biological and Chemical Systems\u2014Biological Information Processing, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcha","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Research Institute for Oncology and Reproduction, Maastricht University, 6229 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Callegaro","sequence":"additional","affiliation":[{"name":"Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6118-0290","authenticated-orcid":false,"given":"Jonathan H.","family":"Freedman","sequence":"additional","affiliation":[{"name":"Centre for Environmental Research and Justice and School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6904-8833","authenticated-orcid":false,"given":"Rita","family":"Ortega-Vallbona","sequence":"additional","affiliation":[{"name":"ProtoQSAR SL, Parque Tecnol\u00f3gico de Valencia, 46980 Paterna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Palomino-Sch\u00e4tzlein","sequence":"additional","affiliation":[{"name":"ProtoQSAR SL, Parque Tecnol\u00f3gico de Valencia, 46980 Paterna, Spain"},{"name":"MolDrug AI Systems SL, 46018 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-0466","authenticated-orcid":false,"given":"Florian","family":"Caiment","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Research Institute for Oncology and Reproduction, Maastricht University, 6229 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Weiss","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems\u2014Biological Information Processing, Karlsruhe Institute of Technology (KIT), 76344 Eggenstein-Leopoldshafen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A Multisociety Delphi Consensus Statement on New Fatty Liver Disease Nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.3350\/cmh.2022.0367","article-title":"MAFLD: How Is It Different from NAFLD?","volume":"29","author":"Gofton","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jhep.2023.10.011","article-title":"MASLD Emerging from the Fog of Fatty Liver","volume":"80","author":"Marchesini","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mej\u00eda-Guzm\u00e1n, J.E., Belmont-Hern\u00e1ndez, R.A., Ch\u00e1vez-Tapia, N.C., Uribe, M., and Nu\u00f1o-L\u00e1mbarri, N. (2025). Metabolic-Dysfunction-Associated Steatotic Liver Disease: Molecular Mechanisms, Clinical Implications, and Emerging Therapeutic Strategies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26072959"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3350\/cmh.2022.0365","article-title":"Global Incidence and Prevalence of Nonalcoholic Fatty Liver Disease","volume":"29","author":"Teng","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.3350\/cmh.2022.0424","article-title":"Non-Alcoholic Fatty Liver Disease: Definition and Subtypes","volume":"29","author":"Han","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/j.jhep.2021.01.045","article-title":"Diagnosis and Management of Secondary Causes of Steatohepatitis","volume":"74","author":"Liebe","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3920196","DOI":"10.1155\/2020\/3920196","article-title":"The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)","volume":"2020","author":"Tanase","year":"2020","journal-title":"J. Diabetes Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1152\/ajpgi.00358.2018","article-title":"Hepatic Transcriptome Signatures in Patients with Varying Degrees of Nonalcoholic Fatty Liver Disease Compared with Healthy Normal-Weight Individuals","volume":"316","author":"Suppli","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.14218\/JCTH.2021.00268","article-title":"Coagulation and Endothelial Dysfunction Associated with NAFLD: Current Status and Therapeutic Implications","volume":"10","author":"Ogresta","year":"2022","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rong, L., Zou, J., Ran, W., Qi, X., Chen, Y., Cui, H., and Guo, J. (2023). Advancements in the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD). Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1087260"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.jhep.2015.11.004","article-title":"EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease","volume":"64","author":"Marchesini","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The Multiple-Hit Pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/hep.31518","article-title":"Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade","volume":"73","author":"Tilg","year":"2021","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/toxres\/tfac087","article-title":"Risk Assessment in the 21st Century: Where Are We Heading?","volume":"12","author":"Brescia","year":"2023","journal-title":"Toxicol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cotox.2019.02.003","article-title":"Regulatory Use and Acceptance of Alternative Methods for Chemical Hazard Identification","volume":"15","author":"Browne","year":"2019","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.envres.2019.03.025","article-title":"Toxicogenomics\u2014What Added Value Do These Approaches Provide for Carcinogen Risk Assessment?","volume":"173","year":"2019","journal-title":"Environ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00204-017-2106-7","article-title":"Microscopy-Based High-Throughput Assays Enable Multi-Parametric Analysis to Assess Adverse Effects of Nanomaterials in Various Cell Lines","volume":"92","author":"Hansjosten","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.toxlet.2010.06.001","article-title":"Polybrominated Diphenyl Ethers and Arylhydrocarbon Receptor Agonists: Different Toxicity and Target Gene Expression","volume":"198","author":"Wahl","year":"2010","journal-title":"Toxicol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.chemosphere.2008.05.025","article-title":"A Technical Mixture of 2,2\u2032,4,4\u2032-Tetrabromo Diphenyl Ether (BDE47) and Brominated Furans Triggers Aryl Hydrocarbon Receptor (AhR) Mediated Gene Expression and Toxicity","volume":"73","author":"Wahl","year":"2008","journal-title":"Chemosphere"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"108169","DOI":"10.1016\/j.envint.2023.108169","article-title":"Systems Toxicology of Complex Wood Combustion Aerosol Reveals Gaseous Carbonyl Compounds as Critical Constituents","volume":"179","author":"Dilger","year":"2023","journal-title":"Environ. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12989-020-00355-1","article-title":"Influence of Wood Species on Toxicity of Log-Wood Stove Combustion Aerosols: A Parallel Animal and Air-Liquid Interface Cell Exposure Study on Spruce and Pine Smoke","volume":"17","author":"Ihantola","year":"2020","journal-title":"Part. Fibre Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3697","DOI":"10.1007\/s00204-017-2020-z","article-title":"Adverse Outcome Pathways: A Concise Introduction for Toxicologists","volume":"91","author":"Vinken","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/etc.34","article-title":"Adverse Outcome Pathways: A Conceptual Framework to Support Ecotoxicology Research and Risk Assessment","volume":"29","author":"Ankley","year":"2010","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1007\/s00204-017-2045-3","article-title":"Adverse Outcome Pathways: Opportunities, Limitations and Open Questions","volume":"91","author":"Leist","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"153814","DOI":"10.1016\/j.tox.2024.153814","article-title":"A Quantitative Weight-of-Evidence Method for Confidence Assessment of Adverse Outcome Pathway Networks: A Case Study on Chemical-Induced Liver Steatosis","volume":"505","author":"Verhoeven","year":"2024","journal-title":"Toxicology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3109\/10408444.2015.1089471","article-title":"The Identification of Nuclear Receptors Associated with Hepatic Steatosis to Develop and Extend Adverse Outcome Pathways","volume":"46","author":"Mellor","year":"2016","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cotox.2019.03.005","article-title":"Paradigm Shift in Safety Assessment Using New Approach Methods: The EU-ToxRisk Strategy","volume":"15","author":"Graepel","year":"2019","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154237","DOI":"10.1016\/j.tox.2025.154237","article-title":"Machine Learning Classification of Steatogenic Compounds Using Toxicogenomics Profiles","volume":"517","author":"Bwanya","year":"2025","journal-title":"Toxicology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41597-022-01825-1","article-title":"Multi-Omics HeCaToS Dataset of Repeated Dose Toxicity for Cardiotoxic & Hepatotoxic Compounds","volume":"9","author":"Verheijen","year":"2022","journal-title":"Sci. Data"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Federico, A., Serra, A., Ha, M.K., Kohonen, P., Choi, J.S., Liampa, I., Nymark, P., Sanabria, N., Cattelani, L., and Fratello, M. (2020). Transcriptomics in Toxicogenomics, Part II: Preprocessing and Differential Expression Analysis for High Quality Data. Nanomaterials, 10.","DOI":"10.3390\/nano10050903"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.tox.2008.05.013","article-title":"A Toxicogenomics Approach for Early Assessment of Potential Non-Genotoxic Hepatocarcinogenicity of Chemicals in Rats","volume":"250","author":"Uehara","year":"2008","journal-title":"Toxicology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/mnfr.200900169","article-title":"The Japanese Toxicogenomics Project: Application of Toxicogenomics","volume":"54","author":"Uehara","year":"2010","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1289\/ehp.1409157","article-title":"Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms","volume":"124","author":"Grossmann","year":"2016","journal-title":"Environ. Health Perspect."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/tpj.2013.39","article-title":"Data Mining Reveals a Network of Early-Response Genes as a Consensus Signature of Drug-Induced in Vitro and in Vivo Toxicity","volume":"14","author":"Zhang","year":"2014","journal-title":"Pharmacogenomics J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ghosh, S., De Smedt, J., Tricot, T., Proen\u00e7a, S., Kumar, M., Nami, F., Vanwelden, T., Vidal, N., Jennings, P., and Kramer, N.I. (2022). Hipsc-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity. Toxics, 10.","DOI":"10.3390\/toxics10010001"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101303","DOI":"10.1016\/j.plipres.2024.101303","article-title":"Lipid Sensing by PPAR\u03b1: Role in Controlling Hepatocyte Gene Regulatory Networks and the Metabolic Response to Fasting","volume":"96","author":"Fougerat","year":"2024","journal-title":"Prog. Lipid Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"154338","DOI":"10.1016\/j.metabol.2020.154338","article-title":"The Role of Peroxisome Proliferator-Activated Receptors (PPAR) in Immune Responses","volume":"114","author":"Christofides","year":"2021","journal-title":"Metabolism"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/35013000","article-title":"Roles of PPARS in Health and Disease","volume":"405","author":"Kersten","year":"2000","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.cmet.2008.03.003","article-title":"Hepatic Steatosis in Leptin-Deficient Mice Is Promoted by the PPAR\u03b3 Target Gene Fsp27","volume":"7","author":"Matsusue","year":"2008","journal-title":"Cell Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108391","DOI":"10.1016\/j.pharmthera.2023.108391","article-title":"PPAR-\u03b3 Signaling in Nonalcoholic Fatty Liver Disease: Pathogenesis and Therapeutic Targets","volume":"245","author":"Chen","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"117089","DOI":"10.1016\/j.biopha.2024.117089","article-title":"Roles of the Peroxisome Proliferator-Activated Receptors (PPARs) in the Pathogenesis of Hepatocellular Carcinoma (HCC)","volume":"177","author":"Pan","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_44","first-page":"1573","article-title":"Mechanisms of Amiodarone and Valproic Acid Induced Liver Steatosis in Mouse in Vivo Act as a Template for Other Hepatotoxicity Models","volume":"88","author":"Vitins","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1080\/03602532.2021.1894571","article-title":"Toxicogenomics of Drug Induced Liver Injury\u2014From Mechanistic Understanding to Early Prediction","volume":"53","author":"Lauschke","year":"2021","journal-title":"Drug Metab. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/s42255-023-00775-1","article-title":"A Proteo-Transcriptomic Map of Non-Alcoholic Fatty Liver Disease Signatures","volume":"5","author":"Govaere","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e35453","DOI":"10.1016\/j.heliyon.2024.e35453","article-title":"Comprehensive Analysis of Shared Risk Genes and Immunity-Metabolisms between Non-Alcoholic Fatty Liver Disease and Atherosclerosis via Bulk and Single-Cell Transcriptome Analyses","volume":"10","author":"Hu","year":"2024","journal-title":"Heliyon"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"W168","DOI":"10.1093\/nar\/gkad393","article-title":"Enrichr-KG: Bridging Enrichment Analysis across Multiple Libraries","volume":"51","author":"Evangelista","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2217\/fca-2017-0019","article-title":"PPARs: Regulators of Metabolism and as Therapeutic Targets in Cardiovascular Disease. Part II: PPAR-\u03b2\/\u03b4 and PPAR-\u03b3","volume":"13","author":"Han","year":"2017","journal-title":"Future Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1007\/s00204-023-03474-8","article-title":"Metabolomics-Based Strategy to Assess Drug Hepatotoxicity and Uncover the Mechanisms of Hepatotoxicity Involved","volume":"97","author":"Moro","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/s41575-021-00502-9","article-title":"Metabolomics and Lipidomics in NAFLD: Biomarkers and Non-Invasive Diagnostic Tests","volume":"18","author":"Masoodi","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_52","first-page":"e29696","article-title":"The Role of Glutathione Metabolism in Chronic Illness Development and Its Potential Use as a Novel Therapeutic Target","volume":"14","author":"Hristov","year":"2022","journal-title":"Cureus"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Va\u0161kov\u00e1, J., Ko\u010dan, L., Va\u0161ko, L., and Perj\u00e9si, P. (2023). Glutathione-Related Enzymes and Proteins: A Review. Molecules, 28.","DOI":"10.3390\/molecules28031447"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"117443","DOI":"10.1016\/j.lfs.2020.117443","article-title":"The Mechanisms of Lysophosphatidylcholine in the Development of Diseases","volume":"247","author":"Liu","year":"2020","journal-title":"Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"D921","DOI":"10.1093\/nar\/gku955","article-title":"Open TG-GATEs: A Large-Scale Toxicogenomics Database","volume":"43","author":"Igarashi","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2131\/jts.31.471","article-title":"Profiling Of Gene Expression In Rat Liver And Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators","volume":"31","author":"Tamura","year":"2006","journal-title":"J. Toxicol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1177\/0960327107087910","article-title":"Species-Specific Differences in Coumarin-Induced Hepatotoxicity as an Example Toxicogenomics-Based Approach to Assessing Risk of Toxicity to Humans","volume":"27","author":"Uehara","year":"2008","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"105143","DOI":"10.1016\/j.yrtph.2022.105143","article-title":"R-ODAF: Omics Data Analysis Framework for Regulatory Application","volume":"131","author":"Verheijen","year":"2022","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41596-018-0103-9","article-title":"Pathway Enrichment Analysis and Visualization of Omics Data Using g:Profiler, GSEA, Cytoscape and EnrichmentMap","volume":"14","author":"Reimand","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"D679","DOI":"10.1093\/nar\/gkad960","article-title":"WikiPathways 2024: Next Generation Pathway Database","volume":"52","author":"Agrawal","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) Hallmark Gene Set Collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"711","DOI":"10.12688\/f1000research.122949.1","article-title":"DEVEA: An Interactive Shiny Application for Differential Expression Analysis, Data Visualization and Enrichment Analysis of Transcriptomics Data","volume":"11","author":"Deleuze","year":"2022","journal-title":"F1000Research"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and Collaborative HTML5 Gene List Enrichment Analysis Tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1002\/cpz1.90","article-title":"Gene Set Knowledge Discovery with Enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1002\/pro.3715","article-title":"Toward Understanding the Origin and Evolution of Cellular Organisms","volume":"28","author":"Kanehisa","year":"2019","journal-title":"Protein Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkae909","article-title":"KEGG: Biological Systems Database as a Model of the Real World","volume":"53","author":"Kanehisa","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"R7","DOI":"10.1186\/gb-2004-6-1-r7","article-title":"The Mammalian Phenotype Ontology as a Tool for Annotating, Analyzing and Comparing Phenotypic Information","volume":"6","author":"Smith","year":"2005","journal-title":"Genome Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinforma."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D Graphics Environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2307\/2331554","article-title":"The Probable Error of a Mean","volume":"6","author":"Student","year":"1908","journal-title":"Biometrika"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"McKnight, P.E., and Najab, J. (2010). Mann-Whitney U Test. The Corsini Encyclopedia of Psychology, John Wiley & Sons, Ltd.","DOI":"10.1002\/9780470479216.corpsy0524"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3825\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:37:19Z","timestamp":1777376239000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3825"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,25]]},"references-count":73,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093825"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093825","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,25]]}}}