{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:04:38Z","timestamp":1789751078218,"version":"4.0.1"},"reference-count":46,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22304061"],"award-info":[{"award-number":["22304061"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22525602"],"award-info":[{"award-number":["22525602"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LMS25H280002"],"award-info":[{"award-number":["LMS25H280002"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhejiang Province Traditional Chinese Medicine Science and Technology Project","award":["2025ZR041"],"award-info":[{"award-number":["2025ZR041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Triphenyltin chloride (TPTC), a member of the organotin family, has been widely restricted due to its endocrine-disrupting effects. Nevertheless, TPTC continues to be detected in aquatic environments and poses potential health risks owing to its persistence and bioaccumulation. Although previous studies have shown that triphenyltin compounds can disrupt lipid homeostasis through nuclear receptor pathways involving retinoid X receptor (RXR) and peroxisome proliferator-activated receptors (PPARs), whether TPTC exerts hepatocytotoxicity through direct metabolic targets remains unclear. This study employed a metabolomics-driven target discovery strategy to analyze intracellular metabolite extracts from HepG2 cells exposed to TPTC for 24 h, aiming to investigate the underlying molecular mechanisms of TPTC-induced metabolic toxicity. Untargeted global metabolomics analysis revealed that TPTC exposure caused significant disturbances in hepatic lipid metabolism, characterized by the accumulation of medium- and long-chain fatty acids and depletion of key metabolites associated with fatty acid \u03b2-oxidation. Pathway enrichment analysis and protein\u2013protein interaction network analysis further indicated that two mitochondrial dehydrogenases involved in fatty acid catabolism\u2500hydroxysteroid 17\u03b2-dehydrogenase 10 (HSD17B10) and hydroxyacyl-CoA dehydrogenase (HADH)\u2500are potential metabolic targets responsible for the observed alterations. Molecular docking, surface plasmon resonance, and cellular thermal shift assays confirmed direct interactions between TPTC and both HSD17B10 and HADH, with binding affinities at the micromolar level. Functional validation demonstrated that TPTC disrupts mitochondrial respiratory function and redox balance by interfering with HADH- and HSD17B10-dependent generation of acetyl-CoA and NADH, leading to mitochondrial dysfunction and oxidative stress. In summary, this study reveals a previously underappreciated mechanism of TPTC toxicity involving mitochondrial metabolism, extending the current understanding of its toxicological pathways beyond nuclear receptor-mediated signaling to include direct disruption of mitochondrial energy and redox metabolism.<\/jats:p>","DOI":"10.1021\/envhealth.5c00823","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T15:18:46Z","timestamp":1778167126000},"page":"1987-1998","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomics-Driven Discovery of Targets for Hepatocytotoxicity\nInduced by Triphenyltin Chloride through Mitochondrial Function Involving\nHSD17B10 and HADH"],"prefix":"10.1021","volume":"4","author":[{"given":"Yanwei","family":"Wang","sequence":"first","affiliation":[{"name":"Jiaxing University , , ,","place":["Jiaxing, China, 314001"]},{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , ,","place":["Hangzhou, China, 310053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Pan","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3212-568X","authenticated-orcid":true,"given":"Tengfei","family":"Xu","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2204-9783","authenticated-orcid":true,"given":"Mingliang","family":"Fang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"2026091808061445000_cit1","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.chemosphere.2017.05.117","article-title":"In vitro evaluation of the cytotoxic\nand bactericidal mechanism of the commonly used pesticide triphenyltin\nhydroxide","volume":"183","author":"Mahanty","year":"2017","journal-title":"Chemosphere"},{"key":"2026091808061445000_cit2","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1016\/j.scitotenv.2016.06.209","article-title":"Imposex and\norganotin compounds in ports of the Mediterranean and the Atlantic:\nIs the story over?","volume":"569\u2013570","author":"Anastasiou","year":"2016","journal-title":"Sci. Total Environ."},{"issue":"4","key":"2026091808061445000_cit3","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1080\/10937400490452705","article-title":"Triphenyltin as a potential human endocrine disruptor","volume":"7","author":"Golub","year":"2004","journal-title":"J. Toxicol Environ. Health B Crit Rev."},{"issue":"1","key":"2026091808061445000_cit4","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.envres.2005.07.004","article-title":"Effects of\nfentin hydroxide on reproduction of the Japanese quail (Coturnix coturnix\njaponica)","volume":"101","author":"Grote","year":"2006","journal-title":"Environ. Res."},{"issue":"1","key":"2026091808061445000_cit5","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.yrtph.2007.05.006","article-title":"Developmental\ntoxicity of triphenyltin hydroxide in mice","volume":"49","author":"Sarpa","year":"2007","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"7","key":"2026091808061445000_cit6","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/S0025-326X(01)00330-7","article-title":"Organotin\nand Irgarol-1051 contamination\nin Singapore coastal waters","volume":"44","author":"Basheer","year":"2002","journal-title":"Mar. Pollut. Bull."},{"issue":"9","key":"2026091808061445000_cit7","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1094\/PDIS-12-18-2282-RE","article-title":"Fungicide Sensitivity Monitoring\nof Alternaria spp. Causing Leaf Spot of Sugarbeet (Beta vulgaris)\nin the Upper Great Lakes","volume":"103","author":"Rosenzweig","year":"2019","journal-title":"Plant Dis"},{"issue":"Pt B","key":"2026091808061445000_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jenvman.2022.116665","article-title":"The last 50 years of organic contamination\nof a highly anthropized tributary of the Po River (Italy)","volume":"326","author":"Vigano\u0300","year":"2023","journal-title":"J. Environ. 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Total Environ."},{"issue":"4","key":"2026091808061445000_cit12","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1007\/s10646-017-1780-9","article-title":"Triphenyltin\nhydroxide induces changes\nin the oxidative stress parameters of fish","volume":"26","author":"Clasen","year":"2017","journal-title":"Ecotoxicology"},{"key":"2026091808061445000_cit13","doi-asserted-by":"publisher","DOI":"10.1016\/j.pestbp.2023.105739","article-title":"TMT-based quantitative proteomics analysis of Sprague-Dawley\nrats\nliver reveals Triphenyltin induced liver damage and lipid metabolism\ndisorders","volume":"198","author":"Ren","year":"2024","journal-title":"Pestic. Biochem. 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Technol."},{"key":"2026091808061445000_cit26","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2022.111356","article-title":"Quorum Sensing\n(QS)-regulated target predictions of Hafnia alvei H4 based on the\njoint application of genome and STRING database","volume":"157","author":"Yan","year":"2022","journal-title":"Food Res. Int."},{"issue":"2","key":"2026091808061445000_cit27","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1021\/acs.est.1c06147","article-title":"Molecular\nDocking\nas a Tool to Examine Organic Cation Sorption to Organic Matter","volume":"56","author":"Scott","year":"2022","journal-title":"Environ. Sci. 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Pers\nMed."},{"key":"2026091808061445000_cit39","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2023.163783","article-title":"Toxic effects of triphenyltin\non the development of zebrafish (Danio\nrerio) embryos","volume":"885","author":"Qiao","year":"2023","journal-title":"Sci. Total Environ."},{"key":"2026091808061445000_cit40","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2019.134140","article-title":"Disruptive effects\nof two organotin pesticides on the\nthyroid signaling pathway in Xenopus laevis during metamorphosis","volume":"697","author":"Li","year":"2019","journal-title":"Sci. Total Environ."},{"issue":"19","key":"2026091808061445000_cit41","doi-asserted-by":"publisher","first-page":"9399","DOI":"10.1021\/acs.est.4c12957","article-title":"Microcystin-LR Induces\nLipid Metabolism Disorder in Pelophylax nigromaculatus Tadpoles via\nthe Gut-Liver Axis","volume":"59","author":"Shu","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"2026091808061445000_cit42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2025.119359","article-title":"Metabolomics analysis\nreveals lipid metabolism disorders caused by triphenyltin via upregulation\nof PPAR\u03b3 pathway","volume":"306","author":"Liu","year":"2025","journal-title":"Ecotoxicol Environ.\nSaf"},{"issue":"5","key":"2026091808061445000_cit43","doi-asserted-by":"publisher","first-page":"2260","DOI":"10.1021\/acs.est.3c08498","article-title":"Assessment of Fetal\nExposure and Elimination of Perfluoroalkyl and\nPolyfluoroalkyl Substances: New Evidence from Paired Serum, Placenta,\nand Meconium Samples","volume":"58","author":"Li","year":"2024","journal-title":"Environ. Sci. Technol."},{"issue":"23","key":"2026091808061445000_cit44","doi-asserted-by":"publisher","first-page":"10227","DOI":"10.1021\/acs.est.3c10973","article-title":"Identification of Hydrocarbon\nSulfonates as Previously Overlooked Transthyretin Ligands in the Environment","volume":"58","author":"Gong","year":"2024","journal-title":"Environ. Sci. Technol."},{"key":"2026091808061445000_cit45","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.envint.2013.06.004","article-title":"Accumulation\nof perfluoroalkyl substances in human tissues","volume":"59","author":"Pe\u0301rez","year":"2013","journal-title":"Environ. Int."},{"key":"2026091808061445000_cit46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2025.119382","article-title":"Effects of metabolic\noverload and\ndetoxification paralysis mechanisms of PAHs on the physiological immunity\nof large yellow croaker","volume":"306","author":"Huang","year":"2025","journal-title":"Ecotoxicol Environ.\nSaf"}],"container-title":["Environment &amp; Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/envhealth.5c00823","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ehnea2\/article-pdf\/4\/9\/1987\/63157860\/envhealth.5c00823.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ehnea2\/article-pdf\/4\/9\/1987\/63157860\/envhealth.5c00823.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:10:02Z","timestamp":1789747802000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ehnea2\/article\/4\/9\/1987\/5072379\/Metabolomics-Driven-Discovery-of-Targets-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":46,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5,7]]},"published-print":{"date-parts":[[2026,9,18]]}},"URL":"https:\/\/doi.org\/10.1021\/envhealth.5c00823","relation":{},"ISSN":["2833-8278"],"issn-type":[{"value":"2833-8278","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]}}}