{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:57Z","timestamp":1785403137282,"version":"3.56.0"},"reference-count":70,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270657"],"award-info":[{"award-number":["82270657"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82270657"],"award-info":[{"award-number":["82270657"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"the Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2025JJ50673"],"award-info":[{"award-number":["2025JJ50673"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polyethylene terephthalate microplastics (PET-MPs) are emerging environmental pollutants, but the molecular mechanisms underlying their hepatotoxicity remain poorly understood. Here, we combined network toxicology with experimental validation to investigate how PET-MPs induce liver injury. In silico, we investigated the PET-repeating unit as the molecular basis for target interactions. We identified 59 overlapping genes between 157 putative PET-MPs targets and 1693 liver injury-associated genes. Protein\u2013protein interaction analysis revealed six hub genes (AKT1, PIK3CA, PIK3CB, PIK3CD, PIK3R1, and SRC), all components of the PI3K\/AKT signaling pathway. Gene ontology analysis showed that PET-MPs affect cellular stress responses and kinase activities, while pathway enrichment analysis identified PI3K-Akt, Ras, and reactive oxygen species pathways as primary targets. Molecular docking demonstrated strong binding affinity between PET-MPs and these core targets (binding free energies &lt;\u22125 kcal\/mol). In vitro, PET-MPs induced mitochondrial depolarization, oxidative stress, upregulation of TNF-\u03b1 and IL-6, and decreased p-AKT\/AKT ratio, accompanied by increased apoptosis; the apoptotic effect was reversed by the AKT agonist SC79. In vivo experiments confirmed that AKT activation reduced PET-MP-induced liver injury, evidenced by decreased inflammation, lower serum transaminases, and restored oxidative balance. These protective effects were abolished by PI3K\/AKT pathway inhibitors. Our study identifies potential therapeutic targets and strategies for PET-MP-induced liver injury.<\/jats:p>","DOI":"10.3390\/ijms27073256","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T02:06:21Z","timestamp":1775441181000},"page":"3256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatotoxic Mechanisms of Polyethylene Terephthalate Microplastics Revealed by Network Toxicology, Molecular Docking, and In Vivo Validation"],"prefix":"10.3390","volume":"27","author":[{"given":"Xuemei","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingying","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7364-3607","authenticated-orcid":false,"given":"Xueting","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouhua","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113267","DOI":"10.1016\/j.jenvman.2021.113267","article-title":"Progress in the catalytic glycolysis of polyethylene terephthalate","volume":"296","author":"Xin","year":"2021","journal-title":"J. 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