{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:48:36Z","timestamp":1785415716771,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Postgraduate Research and Innovation Project of Central South University","award":["2026zzts0639"],"award-info":[{"award-number":["2026zzts0639"]}]},{"award":["2026zzts0639"],"award-info":[{"award-number":["2026zzts0639"]}],"id":[{"id":"https:\/\/ror.org\/00f1zfq44","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>6PPD and its ozonation product 6PPD-quinone (6PPD-Q) are ubiquitous tire-derived pollutants linked to environmental and potential human health risks. This study systematically investigated their mechanisms in lipid-metabolism-related diseases (atherosclerosis, type 2 diabetes, and nonalcoholic fatty liver disease) through network toxicology, transcriptomic validation, molecular docking, and experimental models. Targets of 6PPD and 6PPD-Q were predicted using multiple databases and intersected with disease-associated genes. Protein\u2013protein interaction networks, hub gene screening, GO\/KEGG enrichment, and GEO transcriptomic datasets identified key shared core targets, including PTGS2, MMP9, CXCL8 (for 6PPD), MAPK14, and PTGS2 (for 6PPD-Q). Molecular docking suggested potential strong binding affinities. Integrative analysis highlighted convergence on oxidative stress, inflammation, lipid dysregulation, and MAPK signaling. In vivo, 40-day exposure to 6PPD and 6PPD-Q in C57BL\/6 mice induced hepatic steatosis, elevated serum TC, LDL-C, and HDL-C, upregulated inflammatory cytokines (TNF-\u03b1, IL1B, IL6, and IFNG), and core targets. In vitro, both compounds caused dose-dependent cytotoxicity, ROS accumulation, glutathione redox imbalance, and pro-inflammatory activation. These findings suggest that 6PPD and 6PPD-Q may contribute to lipid-metabolism-related toxic responses through shared and distinct processes involving oxidative stress, inflammatory activation, and lipid dysregulation. These results provide preliminary mechanistic insights into their metabolic toxicity and support further experimental evaluation for environmental health risk assessment.<\/jats:p>","DOI":"10.3390\/ijms27156712","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:11:56Z","timestamp":1785168716000},"page":"6712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling the Molecular Mechanism of 6PPD and 6PPD-Q in Lipid-Metabolism-Related Diseases Through Network Toxicology and Experimental Validation"],"prefix":"10.3390","volume":"27","author":[{"given":"Ze","family":"Li","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8439-1082","authenticated-orcid":false,"given":"Jianan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Xiangya School of Medicine, Central South University, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiangya School of Medicine, Central South University, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108677","DOI":"10.1016\/j.envint.2024.108677","article-title":"Environmental profiles, hazard identification, and toxicological hallmarks of emerging tire rubber-related contaminants 6PPD and 6PPD-quinone","volume":"187","author":"Jiang","year":"2024","journal-title":"Environ. 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