{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:18:17Z","timestamp":1787894297646,"version":"build-2784847793"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is used as a nonreactive brominated flame retardant used in industrial products, particularly in flexible polyvinyl chloride and rigid and flexible polyurethane foams. Although TBPH exposure poses potential health risks, its association with atherosclerosis remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study integrated network toxicology, machine learning, molecular docking, and molecular dynamics (MD) simulations to elucidate the influence of TBPH on high-fat diet\u2013induced atherosclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TBPH exhibited significant predicted toxicity across multiple organs. In total, 167 potential TBPH targets and 690 atherosclerosis-associated targets were identified, with 108 overlapping targets obtained through intersectional analysis. A PPI network was constructed based on these 108 overlapping genes, and the top 20 hub genes were identified. In a parallel independent analysis using a public transcriptomic dataset, 111 differentially expressed genes (DEGs) were identified by comparing atherosclerotic and normal tissues. Subsequent intersection analysis of the 108 overlapping targets and 111 DEGs identified candidate genes that were both TBPH-related and differentially expressed in atherosclerosis. Public transcriptomic data showed higher matrix metalloproteinase 9 (MMP9) level in atherosclerotic tissues. The corresponding receiver operating characteristic (ROC) curve yielded an AUC of 0.806 (95% confidence interval [CI]: 0.698\u20130.914). Molecular docking and MD simulations indicated favorable predicted binding modes and computational stability between TBPH and MMP9. In vivo experiments further demonstrated an association between TBPH exposure, increased MMP9 expression, and high\u2013fat diet\u2013induced atherosclerotic lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings suggest that TBPH may be associated with high-fat diet\u2013induced atherosclerosis progression through the dysregulation of key mediators, providing insight into environmental pollutant\u2013driven disease development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1884077","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:33:33Z","timestamp":1787891613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association between TBPH exposure, increased MMP9 expression, and atherosclerosis: evidence from integrated network analysis and in vivo experiments"],"prefix":"10.3389","volume":"17","author":[{"given":"Huichao","family":"Pan","sequence":"first","affiliation":[{"name":"Division of Cardiology, Institute of Cardiovascular Diseases, Tongren Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Institute of Cardiovascular Diseases, Tongren Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengguang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Gongli Hospital of Shanghai Pudong New Area","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Institute of Cardiovascular Diseases, Tongren Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Institute of Cardiovascular Diseases, Tongren Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Institute of Cardiovascular Diseases, Tongren Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1186\/s12967-023-04755-7","article-title":"Identifying the natural products in the treatment of atherosclerosis by increasing HDL-C level based on bioinformatics analysis, molecular docking, and in vitro experiment","volume":"21","author":"Chen","year":"2023","journal-title":"J. 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