{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T15:35:23Z","timestamp":1775576123025,"version":"3.50.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>This study aims to elucidate the mechanistic role of Per- and Polyfluoroalkyl Substances (PFAS) in the pathogenesis and progression of diabetic kidney disease (DKD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study systematically evaluated the toxicity profiles of PFAS compounds utilizing PubChem, ProTox 3.0, and ChEMBL databases. Potential PFAS-related targets were predicted through SwissTargetPrediction and SuperPred platforms. Gene targets associated with DKD were compiled from the GeneCards and OMIM databases. Intersection analysis of PFAS and DKD-related targets was performed to identify candidate genes. A protein-protein interaction network was constructed using STRING to delineate hub targets. Functional enrichment analyses were subsequently conducted via DAVID to elucidate underlying biological processes and pathways. Validation of hub targets encompassed immunohistochemical staining, single-cell expression profiling, subcellular localization assays, and gene expression analyses using external datasets from the Human Protein Atlas (HPA) and Gene Expression Omnibus (GEO). Furthermore, correlations between immune cell infiltration and gene set enrichment analysis (GSEA) were performed to investigate potential mechanistic links. Finally, molecular docking simulations of PFAS compounds with hub proteins were executed using Discovery Studio and CDOCKER to predict binding interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 424 PFAS-associated targets were identified, alongside 9,999 potential toxic targets related to DKD. KEGG pathway enrichment analysis revealed that PFAS toxicity in DKD is implicated in critical signaling pathways, including nitrogen metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, endocrine resistance, insulin resistance, and AMP-activated protein kinase (AMPK) signaling. Hub targets identified comprised MMP9, BCL2, CYP3A43, ACE, HNF4A, HSP90AA1, AGTR1, MMP2, AGTR2, and HMGCR. GSEA further indicated that these hub targets may contribute to immune-mediated renal injury. Molecular docking simulations substantiated strong binding affinities between PFAS compounds and the identified hub proteins, supporting their potential mechanistic involvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides a theoretical framework for elucidating the toxic targets and underlying mechanisms through which PFAS contribute to the pathogenesis of DKD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1594897","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T04:18:44Z","timestamp":1757391524000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of per- and polyfluoroalkyl substances on diabetic kidney disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Siyuan","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liji","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiqiao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ieam.258","article-title":"Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins","volume":"7","author":"Buck","year":"2011","journal-title":"Integr Environ Assess Manag"},{"key":"B2","doi-asserted-by":"publisher","first-page":"170142","DOI":"10.1016\/j.scitotenv.2024.170142","article-title":"Emergence of per- and poly-fluoroalkyl substances (PFAS) and advances in the remediation strategies","volume":"916","author":"Thapa","year":"2024","journal-title":"Sci Total Environ"},{"key":"B3","doi-asserted-by":"publisher","first-page":"114487","DOI":"10.1016\/j.envpol.2020.114487","article-title":"Novel and legacy per- and polyfluoroalkyl substances (PFASs) in a farmland environment: Soil distribution and biomonitoring with plant leaves and locusts","volume":"263","author":"Lan","year":"2020","journal-title":"Environ pollut"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1021\/acs.est.1c00965","article-title":"First report on the bioaccumulation and trophic transfer of perfluoroalkyl ether carboxylic acids in estuarine food web","volume":"56","author":"Li","year":"2022","journal-title":"Environ Sci Technol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2014.03.030","article-title":"Occurrence and transport of 17 perfluoroalkyl acids in 12 coastal rivers in south Bohai coastal region of China with concentrated fluoropolymer facilities","volume":"190","author":"Wang","year":"2014","journal-title":"Environ pollut"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2017.04.147","article-title":"Perfluoroalkyl and polyfluoroalkyl substances in the lower atmosphere and surface waters of the Chinese Bohai Sea, Yellow Sea, and Yangtze River estuary","author":"Zhao","year":"2017","journal-title":"Sci Total Environ"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1497449","DOI":"10.1155\/2021\/1497449","article-title":"Diabetic nephropathy: challenges in pathogenesis, diagnosis, and treatment","volume":"2021","author":"Samsu","year":"2021","journal-title":"BioMed Res Int"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00125-021-05585-2","article-title":"Interpreting global trends in type 2 diabetes complications and mortality","volume":"65","author":"Ali","year":"2022","journal-title":"Diabetologia"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0135-6","article-title":"Epigenetics and epigenomics in diabetic kidney disease and metabolic memory","volume":"15","author":"Kato","year":"2019","journal-title":"Nat Rev Nephrol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-023-26384-9","article-title":"Exposure to perfluoroalkyl and polyfluoroalkyl substances and estimated glomerular filtration rate in adults: a cross-sectional study based on NHANES (2017-2018)","volume":"30","author":"Liang","year":"2023","journal-title":"Environ Sci pollut Res Int"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2019.02.004","article-title":"Perfluoroalkyl substances are inversely associated with coronary heart disease in adults with diabetes","volume":"33","author":"Honda-Kohmo","year":"2019","journal-title":"J Diabetes Complications"},{"key":"B12","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":"Sci Total Environ"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e2400389","DOI":"10.1002\/advs.202400389","article-title":"A network toxicology approach for mechanistic modelling of nanomaterial hazard and adverse outcomes","volume":"11","author":"Del Giudice","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/1062936X.2012.657237","article-title":"The impact of network biology in pharmacology and toxicology","volume":"23","author":"Panagiotou","year":"2012","journal-title":"SAR QSAR Environ Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"113785","DOI":"10.1016\/j.fct.2023.113785","article-title":"An integrated strategy combining network toxicology and feature-based molecular networking for exploring hepatotoxic constituents and mechanism of Epimedii Folium-induced hepatotoxicity","volume":"176","author":"Zhao","year":"2023","journal-title":"vitro. Food Chem Toxicol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2018.01.018","article-title":"A strategy for the discovery and validation of toxicity quality marker of Chinese medicine based on network toxicology","volume":"54","author":"Li","year":"2019","journal-title":"Phytomedicine"},{"key":"B17","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1002\/jat.4506","article-title":"A novel strategy for the study on molecular mechanism of prostate injury induced by 4,4\u2019-sulfonyldiphenol based on network toxicology analysis","volume":"44","author":"Huang","year":"2024","journal-title":"J Appl Toxicol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 update","volume":"51","author":"Kim","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: a webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1075","article-title":"ChEMBL: towards direct deposition of bioassay data","volume":"47","author":"Mendez","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac297","article-title":"SuperPred 3.0: drug classification and target prediction-a machine learning approach","volume":"50","author":"Gallo","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"117352","DOI":"10.1016\/j.ecoenv.2024.117352","article-title":"Environmental triggers and future risk of developing autoimmune diseases: Molecular mechanism and network toxicology analysis of bisphenol A","volume":"288","author":"Hong","year":"2024","journal-title":"Ecotoxicol Environ Saf"},{"key":"B24","doi-asserted-by":"publisher","first-page":"baq020","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3: the human gene integrator","volume":"2010","author":"Safran","year":"2010","journal-title":"Database (Oxford)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1 2 1","DOI":"10.1002\/cpbi.27","article-title":"Searching online mendelian inheritance in man (OMIM): A knowledgebase of human genes and genetic phenotypes","volume":"58","author":"Amberger","year":"2017","journal-title":"Curr Protoc Bioinf"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"Storey","year":"2003","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4376","DOI":"10.1038\/s41467-019-12235-0","article-title":"Functional interpretation of single cell similarity maps","volume":"10","author":"DeTomaso","year":"2019","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1094","article-title":"STRING v9.1: protein-protein interaction networks, with increased coverage and integration","volume":"41","author":"Franceschini","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","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 Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/35075138","article-title":"Lethality and centrality in protein networks","volume":"411","author":"Jeong","year":"2001","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.1158684","article-title":"High-quality binary protein interaction map of the yeast interactome network","volume":"322","author":"Yu","year":"2008","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nature10011","article-title":"Controllability of complex networks","volume":"473","author":"Liu","year":"2011","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e0137432","DOI":"10.1371\/journal.pone.0137432","article-title":"High throughput sequencing identifies microRNAs mediating alpha-synuclein toxicity by targeting neuroactive-ligand receptor interaction pathway in early stage of drosophila parkinson\u2019s disease model","volume":"10","author":"Kong","year":"2015","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7493-1_12","article-title":"Profiling tumor infiltrating immune cells with CIBERSORT","volume":"1711","author":"Chen","year":"2018","journal-title":"Methods Mol Biol"},{"key":"B36","doi-asserted-by":"publisher","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 U.S.A"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-02014-7","article-title":"Extending support for mouse data in the Molecular Signatures Database (MSigDB)","volume":"20","author":"Castanza","year":"2023","journal-title":"Nat Methods"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.14.114","article-title":"Pharmacophore modeling for COX-1 and -2 inhibitors with LigandScout in comparison to Discovery Studio","volume":"6","author":"Temml","year":"2014","journal-title":"Future Med Chem"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.9b02263","article-title":"Discovery of lonafarnib-like compounds: pharmacophore modeling and molecular dynamics studies","volume":"5","author":"Rampogu","year":"2020","journal-title":"ACS Omega"},{"key":"B40","doi-asserted-by":"publisher","first-page":"115210","DOI":"10.1016\/j.biopha.2023.115210","article-title":"Identification of bioactive compounds and potential mechanisms of scutellariae radix-coptidis rhizoma in the treatment of atherosclerosis by integrating network pharmacology and experimental validation","volume":"165","author":"Ji","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-024-32082-x","article-title":"PFAS: exploration of neurotoxicity and environmental impact","volume":"31","author":"Nannaware","year":"2024","journal-title":"Environ Sci pollut Res Int"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1039\/D0EM00291G","article-title":"An overview of the uses of per- and polyfluoroalkyl substances (PFAS)","volume":"22","author":"Gluge","year":"2020","journal-title":"Environ Sci Process Impacts"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1039\/D1EM00228G","article-title":"Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review","volume":"23","author":"Cao","year":"2021","journal-title":"Environ Sci Process Impacts"},{"key":"B44","doi-asserted-by":"publisher","first-page":"6623010","DOI":"10.1155\/2021\/6623010","article-title":"Network pharmacology-based prediction of mechanism of shenzhuo formula for application to DKD","volume":"2021","author":"Wang","year":"2021","journal-title":"Evid Based Complement Alternat Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41401-021-00721-5","article-title":"Wogonin protects glomerular podocytes by targeting Bcl-2-mediated autophagy and apoptosis in diabetic kidney disease","volume":"43","author":"Liu","year":"2022","journal-title":"Acta Pharmacol Sin"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e36843","DOI":"10.1097\/MD.0000000000036843","article-title":"TYROBP as a molecular target in cholangiocarcinoma, renal cancer and abdominal aortic aneurysm","volume":"103","author":"Jia","year":"2024","journal-title":"Med (Baltimore)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/dom.13983","article-title":"Non-steroidal mineralocorticoid antagonists: Prospects for renoprotection in diabetic kidney disease","author":"Al Dhaybi","year":"2020","journal-title":"Diabetes Obes Metab"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e70649","DOI":"10.1096\/fj.202500106R","article-title":"HNF4A regulated APEH deficiency promotes UPR activation in diabetic kidney disease","volume":"39","author":"Wang","year":"2025","journal-title":"FASEB J"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2421631","DOI":"10.1155\/2020\/2421631","article-title":"A network pharmacology-based strategy for unveiling the mechanisms of tripterygium wilfordii hook F against diabetic kidney disease","volume":"2020","author":"Wang","year":"2020","journal-title":"J Diabetes Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0248-y","article-title":"Targeting the progression of chronic kidney disease","volume":"16","author":"Ruiz-Ortega","year":"2020","journal-title":"Nat Rev Nephrol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.kint.2022.06.008","article-title":"KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease","volume":"102","year":"2022","journal-title":"Kidney Int"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.08.155","article-title":"Polysaccharide isolated from persimmon leaves (Diospyros kaki Thunb.) suppresses TGF-beta1-induced epithelial-to-mesenchymal transition in A549 cells","volume":"164","author":"Lim","year":"2020","journal-title":"Int J Biol Macromol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00758","article-title":"Inhibition of (pro)renin receptor contributes to renoprotective effects of angiotensin II type 1 receptor blockade in diabetic nephropathy","volume":"8","author":"Zhang","year":"2017","journal-title":"Front Physiol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1186\/s12906-020-03155-4","article-title":"Revealing active components, action targets and molecular mechanism of Gandi capsule for treating diabetic nephropathy based on network pharmacology strategy","volume":"20","author":"Zhang","year":"2020","journal-title":"BMC Complement Med Ther"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.08.021","article-title":"An overview of renal metabolomics","volume":"91","author":"Kalim","year":"2017","journal-title":"Kidney Int"},{"key":"B56","doi-asserted-by":"publisher","first-page":"107117","DOI":"10.1016\/j.intimp.2020.107117","article-title":"Bixin attenuates carbon tetrachloride induced oxidative stress, inflammation and fibrosis in kidney by regulating the Nrf2\/TLR4\/MyD88 and PPAR-gamma\/TGF-beta1\/Smad3 pathway","volume":"90","author":"Ma","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.07.027","article-title":"Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-kappaB\/p38 signaling pathway in high-fat diet\/streptozotocin-induced diabetic mice","volume":"63","author":"Song","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/ndt\/gfi265","article-title":"Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases","volume":"21","author":"Ruiz-Ortega","year":"2006","journal-title":"Nephrol Dial Transplant"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1594897\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T04:18:45Z","timestamp":1757391525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1594897\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,9]]},"references-count":58,"alternative-id":["10.3389\/fendo.2025.1594897"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1594897","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,9]]},"article-number":"1594897"}}