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This study presented an integrated computational approach, combining network toxicology, molecular docking, and molecular dynamics simulations to systematically elucidate the molecular mechanisms underlying PFOS induced thyroid toxicity. Through integrated analysis of the Comparative Toxicogenomics Database (CTD), GeneCards, and Online Mendelian Inheritance in Man (OMIM) databases, we identified 205 potential thyroid toxicity-related targets. Protein-protein interaction network analysis revealed 34 hub targets, with TP53, JUN, ESR1, AKT1, and CTNNB1 emerging as central nodes in the toxicity network. Functional enrichment analysis demonstrated significant enrichment in the PPAR signaling pathway, fatty acid metabolism, AGE-RAGE pathway, and AMPK pathway, indicating that PFOS influences thyroid function through multiple signaling pathways. Molecular docking studies showed that PFOS forms stable complexes with core target proteins, with binding energies ranging from \u2212\u20094.9 to -9.7\u00a0kcal\/mol. Molecular dynamics simulations further validated the structural stability of these complexes, with PFOS-AKT1 and PFOS-TP53 exhibiting the highest conformational stability. This study revealed the multi-target and multi-pathway characteristics of PFOS-induced thyroid toxicity, providing novel insights into its toxicological mechanisms.<\/jats:p>","DOI":"10.1038\/s41598-025-92678-2","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T14:06:42Z","timestamp":1741270002000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Integrated computational analysis of molecular mechanisms underlying perfluorooctane sulfonic acid induced thyroid toxicity"],"prefix":"10.1038","volume":"15","author":[{"given":"Haoran","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huicai","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"92678_CR1","doi-asserted-by":"publisher","first-page":"115663","DOI":"10.1016\/j.ecoenv.2023.115663","volume":"267","author":"SYAZ Wee","year":"2023","unstructured":"Wee, S. 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