{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:10:34Z","timestamp":1791929434923,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Postgraduate Research and Innovation Project of Central South University","award":["2026zzts639"],"award-info":[{"award-number":["2026zzts639"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>6PPD is a widely used tire antioxidant that readily transforms into its more toxic ozonation product, 6PPD-quinone (6PPD-Q). Both compounds are emerging environmental contaminants with potential neurotoxic risks, yet their molecular mechanisms in Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) remain unclear. This study integrated network toxicology, molecular docking, transcriptomic validation, and experimental models to investigate their neurotoxic effects. In silico analyses predicted significant neurotoxicity and blood\u2013brain barrier permeability for both compounds. Target prediction and PPI network analysis identified 145\/121 overlapping targets with AD\/PD for 6PPD and 120\/100 for 6PPD-Q. Functional enrichment analysis suggested that 6PPD-associated targets were mainly enriched in axon regeneration-, p75NTR-, and AGE-RAGE-related pathways, whereas 6PPD-Q-associated targets were enriched in MAPK cascade-, endosomal TLR signaling-, and amyloid-\u03b2 formation-related pathways. Molecular docking suggested favorable binding affinities between these compounds and several core targets, including MAP2K1, EGFR, GSK3B, and CYCS. Transcriptomic validation in GEO datasets prioritized multiple hub genes. In vivo experiments showed activation of apoptosis-related signaling in the brain, while in vitro assays demonstrated ROS accumulation and neuroinflammatory activation (elevated TNF-\u03b1, IL-1\u03b2, IL-6, IFN-\u03b3). CYCS and MAP2K1 emerged as key convergent nodes. Our findings reveal distinct yet synergistic neurotoxic mechanisms of 6PPD and 6PPD-Q in AD and PD, highlighting tire-derived pollutants as potential environmental risk factors for neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/toxics14060504","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:33:44Z","timestamp":1781073224000},"page":"504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Molecular Mechanisms of 6PPD and 6PPD-Q Toxicity in Neurodegenerative Diseases: A Network Toxicology and Experimental Validation Study"],"prefix":"10.3390","volume":"14","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":"Xiangya School of Medicine, Central South University, Changsha 410011, 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8380-7859","authenticated-orcid":false,"given":"Dingming","family":"Xue","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, 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":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132265","DOI":"10.1016\/j.jhazmat.2023.132265","article-title":"Tire-rubber related pollutant 6-PPD quinone: A review of its transformation, environmental distribution, bioavailability, and toxicity","volume":"459","author":"Hua","year":"2023","journal-title":"J. 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