{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:32:12Z","timestamp":1793734332213,"version":"4.6.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Chongqing Youth and Middle-aged High-end Talent Program","award":["YXGD202456"],"award-info":[{"award-number":["YXGD202456"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Perfluorooctane sulfonamide (PFOSA) is an environmentally persistent compound that poses a threat to human health, but its hepatotoxicity mechanism remains unclear. This study integrated the National Health and Nutrition Examination Survey (NHANES; USA) epidemiological data, network toxicology, bioinformatics analysis, and molecular docking simulation to systematically explore the hepatotoxicity mechanism of PFOSA from multiple levels. Potential targets of PFOSA and disease targets related to liver injury were screened through multiple databases, a protein\u2013protein interaction network was constructed, core targets were identified, and Gene Ontology (GO)\/Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was conducted. External validation was conducted through the Gene Expression Omnibus dataset, and molecular docking was used to evaluate the affinity between PFOSA and key targets. Data from 2,476 NHANES participants (1999\u20132012) showed that there was a significant association between PFOSA exposure and liver function markers (aspartate aminotransferase, alkaline phosphatase, total bilirubin, etc.), establishing an association between the population level and liver injury. Through multi-database screening (CHEMBL, Search Tool for Interactions of Chemicals, GeneCards, etc.), 623 intersection targets were identified, and 37 core targets were screened out. Among them, the top five were E3 ubiquitin-protein ligase MDM2 (MDM2), **heat shock protein 90 alpha family class B member 1** (*HSP90AB1*), Hypoxia-inducible factor 1-alpha (HIF1A), Matrix metalloproteinase-9 (MMP9), and cellular tumor antigen p53 (TP53). The GO and KEGG analyses highlighted the enrichment of cancer-related pathways, oxidative phosphorylation, and nonalcoholic fatty liver disease (NAFLD). The molecular docking of PFOSA with the core target shows a strong binding affinity. Overall, PFOSA may induce liver steatosis, fibrosis, and carcinogenic risks by disrupting the apoptosis regulation of MDM2-TP53, HIF1A-mediated oxidative stress, and MMP9-driven extracellular matrix degradation. These findings emphasize the necessity of stricter PFOSA regulations and enhanced environmental monitoring in areas where NAFLD is prevalent, providing a framework for toxicity assessment and intervention strategies.<\/jats:p>","DOI":"10.1093\/etojnl\/vgag192","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:28:33Z","timestamp":1784903313000},"page":"3270-3284","source":"Crossref","is-referenced-by-count":0,"title":["Identification of core pathways in perfluorooctane sulfonamide-induced liver injury using a network toxicology approach"],"prefix":"10.1093","volume":"45","author":[{"given":"Yan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzhong","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiling","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9006-2608","authenticated-orcid":false,"given":"Yijie","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Daping Hospital, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"2026110314194244600_vgag192-B1","doi-asserted-by":"publisher","first-page":"34250","DOI":"10.1074\/jbc.M704075200","article-title":"p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis","volume":"282","author":"Amaral","year":"2007","journal-title":"Journal of Biological Chemistry"},{"key":"2026110314194244600_vgag192-B2","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.chemosphere.2016.01.014","article-title":"Occurrence of select perfluoroalkyl substances at U.S. Air Force aqueous film-forming foam release sites other than fire-training areas: Field-validation of critical fate and transport properties","volume":"150","author":"Anderson","year":"2016","journal-title":"Chemosphere"},{"key":"2026110314194244600_vgag192-B3","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/cdd.2017.180","article-title":"Why are there hotspot mutations in the TP53 gene in human cancers?","volume":"25","author":"Baugh","year":"2018","journal-title":"Cell Death & Differentiation"},{"key":"2026110314194244600_vgag192-B4","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3390\/toxics12070501","article-title":"Using zebrafish to screen developmental toxicity of per- and polyfluoroalkyl substances (PFAS)","volume":"12","author":"Britton","year":"2024","journal-title":"Toxics"},{"key":"2026110314194244600_vgag192-B5","doi-asserted-by":"publisher","first-page":"140017","DOI":"10.1016\/j.scitotenv.2020.140017","article-title":"PFAS concentrations in soils: Background levels versus contaminated sites","volume":"740","author":"Brusseau","year":"2020","journal-title":"Science of the Total Environment"},{"key":"2026110314194244600_vgag192-B6","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41420-020-0287-y","article-title":"The role of MDM2-p53 axis dysfunction in the hepatocellular carcinoma transformation","volume":"6","author":"Cao","year":"2020","journal-title":"Cell Death Discovery"},{"key":"2026110314194244600_vgag192-B7","author":"Centers for Disease Control and Prevention","year":"2011"},{"key":"2026110314194244600_vgag192-B8","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1016\/j.biocel.2010.04.015","article-title":"HSP90beta interacts with Rac1 to activate NADPH oxidase in Helicobacter pylori-infected gastric epithelial cells","volume":"42","author":"Cha","year":"2010","journal-title":"International Journal of Biochemistry & Cell Biology"},{"key":"2026110314194244600_vgag192-B9","doi-asserted-by":"publisher","first-page":"8438","DOI":"10.1021\/acs.est.1c08875","article-title":"Perfluorooctane sulfonamide (PFOSA) induces cardiotoxicity via aryl hydrocarbon receptor activation in zebrafish","volume":"56","author":"Chen","year":"2022","journal-title":"Environmental Science & Technology"},{"key":"2026110314194244600_vgag192-B10","doi-asserted-by":"publisher","DOI":"10.1021\/acs.est.4c01153","article-title":"Perfluorooctane sulfonamide induced autotoxic effects on the zebrafish immune system","author":"Chen","year":"2024","journal-title":"Environmental Science & Technology"},{"key":"2026110314194244600_vgag192-B11","doi-asserted-by":"publisher","first-page":"46001","DOI":"10.1289\/ehp10092","article-title":"Exposure to per- and polyfluoroalkyl substances and markers of liver injury: A systematic review and meta-analysis","volume":"130","author":"Costello","year":"2022","journal-title":"Environmental Health Perspectives"},{"key":"2026110314194244600_vgag192-B7821450","author":"Dassault Syst\u00e8mes BIOVIA.","year":"2023","journal-title":"Discovery Studio Modeling Environment"},{"key":"2026110314194244600_vgag192-B13","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/387296a0","article-title":"Mdm2 promotes the rapid degradation of p53","volume":"387","author":"Haupt","year":"1997","journal-title":"Nature"},{"key":"2026110314194244600_vgag192-B14","doi-asserted-by":"publisher","first-page":"167904","DOI":"10.1016\/j.scitotenv.2023.167904","article-title":"Efficient analysis of toxicity and mechanisms of environmental pollutants with network toxicology and molecular docking strategy: Acetyl tributyl citrate as an example","volume":"905","author":"Huang","year":"2023","journal-title":"Science of the Total Environment"},{"key":"2026110314194244600_vgag192-B15","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"2026110314194244600_vgag192-B16","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1620\/tjem.222.319","article-title":"Increased urinary lipocalin-2 reflects matrix metalloproteinase-9 activity in chronic hepatitis C with hepatic fibrosis","volume":"222","author":"Kim","year":"2010","journal-title":"Tohoku Journal of Experimental Medicine"},{"key":"2026110314194244600_vgag192-B17","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1016\/s0002-9440(10)65703-3","article-title":"Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis","volume":"153","author":"Kossakowska","year":"1998","journal-title":"American Journal of Pathology"},{"key":"2026110314194244600_vgag192-B18","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3390\/cimb47020098","article-title":"Dose-dependent PFESA-BP2 exposure increases risk of liver toxicity and hepatocellular carcinoma","volume":"47","author":"Kostecki","year":"2025","journal-title":"Current Issues in Molecular Biology"},{"key":"2026110314194244600_vgag192-B19","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.cell.2009.04.050","article-title":"Modes of p53 regulation","volume":"137","author":"Kruse","year":"2009","journal-title":"Cell"},{"key":"2026110314194244600_vgag192-B20","doi-asserted-by":"publisher","first-page":"E2414","DOI":"10.1073\/pnas.1315605111","article-title":"Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation","volume":"111","author":"Liu","year":"2014","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"2026110314194244600_vgag192-B21","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"Journal of Computational Chemistry"},{"key":"2026110314194244600_vgag192-B5975501","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1096\/fj.201600845R","article-title":"Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis","volume":"31","author":"Prokesch","year":"2017","journal-title":"FASEB"},{"key":"2026110314194244600_vgag192-B22","doi-asserted-by":"publisher","first-page":"105577","DOI":"10.1016\/j.tiv.2023.105577","article-title":"Chronic PFOA exposure in vitro causes acquisition of multiple tumor cell characteristics in rat liver cells","volume":"89","author":"Qu","year":"2023","journal-title":"Toxicology in Vitro"},{"key":"2026110314194244600_vgag192-B23","author":"R Core Team.","year":"2023"},{"key":"2026110314194244600_vgag192-B24","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nature Methods"},{"key":"2026110314194244600_vgag192-B25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1146\/annurev-pathol-012513-104720","article-title":"Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology","volume":"9","author":"Semenza","year":"2014","journal-title":"Annual Review of Pathology"},{"key":"2026110314194244600_vgag192-B26","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Research"},{"key":"2026110314194244600_vgag192-B27","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.ijheh.2012.11.002","article-title":"Expression profiling of selected genes of toxication and detoxication pathways in peripheral blood lymphocytes as a biomarker for predicting toxicity of environmental chemicals","volume":"216","author":"Sharma","year":"2013","journal-title":"International Journal of Hygiene and Environmental Health"},{"key":"2026110314194244600_vgag192-B28","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/bs.pmch.2021.01.004","article-title":"Use of molecular docking computational tools in drug discovery","volume":"60","author":"Stanzione","year":"2021","journal-title":"Progress in Medicinal Chemistry"},{"key":"2026110314194244600_vgag192-B29","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/nrm2918","article-title":"HSP90 at the hub of protein homeostasis: emerging mechanistic insights","volume":"11","author":"Taipale","year":"2010","journal-title":"Nature Reviews. Molecular Cell Biology"},{"key":"2026110314194244600_vgag192-B30","doi-asserted-by":"publisher","first-page":"R1147","DOI":"10.1016\/j.cub.2017.09.019","article-title":"The liver","volume":"27","author":"Trefts","year":"2017","journal-title":"Current Biology"},{"key":"2026110314194244600_vgag192-B31","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"Journal of Computational Chemistry"},{"key":"2026110314194244600_vgag192-B32","doi-asserted-by":"publisher","DOI":"10.3390\/cells12030512","article-title":"The role of TP53 in adaptation and evolution","volume":"12","author":"Voskarides","year":"2023","journal-title":"Cells"},{"key":"2026110314194244600_vgag192-B33","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1124\/pharmrev.123.001026","article-title":"MDM2 inhibitors for cancer therapy: The past, present, and future","volume":"76","author":"Wang","year":"2024","journal-title":"Pharmacological Reviews"},{"key":"2026110314194244600_vgag192-B34","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1097\/ede.0000000000000524","article-title":"Brief report: Plasma concentrations of perfluorooctane sulfonamide and time-to-pregnancy among primiparous women","volume":"27","author":"Whitworth","year":"2016","journal-title":"Epidemiology"},{"key":"2026110314194244600_vgag192-B35","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/cr.2008.62","article-title":"p53's mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity","volume":"18","author":"Wolff","year":"2008","journal-title":"Cell Research"},{"key":"2026110314194244600_vgag192-B36","doi-asserted-by":"publisher","first-page":"132552","DOI":"10.1016\/j.jhazmat.2023.132552","article-title":"Hepatotoxic response of perfluorooctane sulfonamide (PFOSA) in early life stage zebrafish (Danio rerio) is greater than perfluorooctane sulfonate (PFOS)","volume":"461","author":"Xuan","year":"2024","journal-title":"Journal of Hazardous Materials"},{"key":"2026110314194244600_vgag192-B37","doi-asserted-by":"publisher","first-page":"37258","DOI":"10.1074\/jbc.M106089200","article-title":"The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B\/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL","volume":"276","author":"Yan","year":"2001","journal-title":"Journal of Biological Chemistry"},{"key":"2026110314194244600_vgag192-B38","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.lfs.2018.10.051","article-title":"p53 as a double-edged sword in the progression of non-alcoholic fatty liver disease","volume":"215","author":"Yan","year":"2018","journal-title":"Life Sciences"},{"key":"2026110314194244600_vgag192-B39","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1021\/es052067y","article-title":"Perfluorooctanesulfonate and related fluorochemicals in human blood samples from China","volume":"40","author":"Yeung","year":"2006","journal-title":"Environmental Science & Technology"},{"key":"2026110314194244600_vgag192-B40","doi-asserted-by":"publisher","first-page":"e0133882","DOI":"10.1371\/journal.pone.0133882","article-title":"PDIA3 knockdown exacerbates free fatty acid-induced hepatocyte steatosis and apoptosis","volume":"10","author":"Zhang","year":"2015","journal-title":"PloS One"},{"key":"2026110314194244600_vgag192-B41","doi-asserted-by":"publisher","first-page":"123830","DOI":"10.1016\/j.jenvman.2024.123830","article-title":"Assessing the toxicological impact of PET-MPs exposure on IVDD: Insights from network toxicology and molecular docking","volume":"373","author":"Zhang","year":"2025","journal-title":"Journal of Environmental Management"},{"key":"2026110314194244600_vgag192-B42","doi-asserted-by":"publisher","first-page":"124619","DOI":"10.1016\/j.chemosphere.2019.124619","article-title":"Contributions of enzymes and gut microbes to biotransformation of perfluorooctane sulfonamide in earthworms (Eisenia fetida)","volume":"238","author":"Zhao","year":"2020","journal-title":"Chemosphere"},{"key":"2026110314194244600_vgag192-B43","doi-asserted-by":"publisher","first-page":"5769","DOI":"10.7150\/thno.36505","article-title":"Inhibition of HSP90\u03b2 improves lipid disorders by promoting mature SREBPs degradation via the ubiquitin-proteasome system","volume":"9","author":"Zheng","year":"2019","journal-title":"Theranostics"}],"container-title":["Environmental Toxicology and Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/etc\/advance-article-pdf\/doi\/10.1093\/etojnl\/vgag192\/69951267\/vgag192.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/etc\/article-pdf\/45\/11\/3270\/69951267\/vgag192.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/etc\/article-pdf\/45\/11\/3270\/69951267\/vgag192.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:19:50Z","timestamp":1793733590000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/etc\/article\/45\/11\/3270\/8741451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,7,24]]},"published-print":{"date-parts":[[2026,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/etojnl\/vgag192","relation":{},"ISSN":["0730-7268","1552-8618"],"issn-type":[{"value":"0730-7268","type":"print"},{"value":"1552-8618","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,11]]},"published":{"date-parts":[[2026,7,24]]}}}