{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:16Z","timestamp":1760060776329,"version":"build-2065373602"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T00:00:00Z","timestamp":1757203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Guangdong Province Youth Innovation Talent Program for Ordinary Universities","award":["2022KQNCX035"],"award-info":[{"award-number":["2022KQNCX035"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The widespread use of pyrethroid insecticides poses a public health hazard, and previous studies have shown that these insecticides may contribute to liver injury, but the mechanism of action has not been comprehensively investigated. The differentially expressed genes in the GSE102006 dataset and the targets from the GeneCards and OMIM databases were used as relevant targets for drug-induced liver injury (DILI). These targets were intersected with the predicted targets of pyrethroids, and 167 intersecting targets were obtained for protein\u2013protein interaction (PPI) analysis and enrichment analysis. The PPI network consists of 1,378 edges. SRC, NFKB1, MAPK3, RELA are key targets in the network. Pathway enrichment showed that the intersection targets were significantly enriched in cAMP, calcium, PI3K-Akt, and VEGF signaling pathways. These signaling pathways extensively regulate cell growth, reproduction, apoptosis, and mediate inflammatory responses. In addition, this study identified a causal relationship between gene variants in PIM1 and FDFT1 and disease progression by mendelian randomization analysis. The results of molecular docking and molecular dynamics simulation further verify the strong and stable interaction between pyrethroids and these potential targets, suggesting their possible role in the mechanism of pyrethroid-related liver injury. These findings provide a theoretical foundation for future research into biomarkers of pyrethroid-induced DILI.<\/jats:p>","DOI":"10.1093\/toxres\/tfaf143","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:52:52Z","timestamp":1760035972000},"source":"Crossref","is-referenced-by-count":0,"title":["Study of mechanism of drug-induced liver injury caused by pyrethroid insecticides based on network toxicology and mendelian randomization"],"prefix":"10.1093","volume":"14","author":[{"given":"Jian-xing","family":"Li","sequence":"first","affiliation":[{"name":"School of Public Health, Guangdong Pharmaceutical University , No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong 510310 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi-qi","family":"Gan","sequence":"additional","affiliation":[{"name":"School of Public Health, Guangdong Pharmaceutical University , No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong 510310 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2233-9609","authenticated-orcid":false,"given":"Yun","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Public Health, Guangdong Pharmaceutical University , No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong 510310 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"2025100914524545200_ref1","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1001\/jamainternmed.2019.6019","article-title":"Association between exposure to pyrethroid insecticides and risk of all-cause and cause-specific mortality in the general US adult population","volume":"180","author":"Bao","year":"2020","journal-title":"JAMA Intern Med"},{"key":"2025100914524545200_ref2","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.taap.2018.05.007","article-title":"Aggregate exposure of the adult French population to pyrethroids","volume":"351","author":"Darney","year":"2018","journal-title":"Toxicol Appl Pharmacol"},{"key":"2025100914524545200_ref3","doi-asserted-by":"publisher","first-page":"3240","DOI":"10.1021\/acs.est.7b06689","article-title":"Pyrethroid pesticide exposure and risk of primary ovarian insufficiency in Chinese women","volume":"52","author":"Li","year":"2018","journal-title":"Environ Sci Technol"},{"key":"2025100914524545200_ref4","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.tox.2011.04.012","article-title":"Immunomodulation of serum complement (C3) and macrophages by synthetic pyrethroid fenvalerate: in vitro study","volume":"285","author":"Dutta","year":"2011","journal-title":"Toxicology"},{"key":"2025100914524545200_ref5","doi-asserted-by":"publisher","first-page":"173855","DOI":"10.1016\/j.scitotenv.2024.173855","article-title":"Association of pesticide exposure with respiratory health outcomes and rhinitis in avocado farmworkers from Michoac\u00e1n, Mexico","volume":"945","author":"Alcal\u00e1","year":"2024","journal-title":"Sci Total Environ"},{"key":"2025100914524545200_ref6","doi-asserted-by":"publisher","first-page":"876","DOI":"10.5858\/arpa.2014-0214-RA","article-title":"Drug-induced liver injury","volume":"139","author":"Fisher","year":"2015","journal-title":"Arch Pathol Lab Med"},{"key":"2025100914524545200_ref7","doi-asserted-by":"publisher","first-page":"3381","DOI":"10.1007\/s00204-020-02885-1","article-title":"Drug induced liver injury: an update","volume":"94","author":"Garcia-Cortes","year":"2020","journal-title":"Arch Toxicol"},{"key":"2025100914524545200_ref8","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1007\/s40264-017-0547-9","article-title":"The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of Delaware","volume":"40","author":"Vega","year":"2017","journal-title":"Drug Saf"},{"key":"2025100914524545200_ref9","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1038\/ajg.2012.138","article-title":"A prospective nationwide study of drug-induced liver injury in Korea","volume":"107","author":"Suk","year":"2012","journal-title":"Am J Gastroenterol"},{"key":"2025100914524545200_ref10","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s40360-022-00586-2","article-title":"Long-term low-dose exposure of permethrin induces liver and kidney damage in rats","volume":"23","author":"Sun","year":"2022","journal-title":"BMC Pharmacol Toxicol"},{"key":"2025100914524545200_ref11","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.pestbp.2014.12.028","article-title":"Multilevel evaluations of potential liver injury of bifenthrin","volume":"122","author":"Zhang","year":"2015","journal-title":"Pestic Biochem Physiol"},{"key":"2025100914524545200_ref12","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3390\/toxics12040258","article-title":"Natural pyrethrin-induced oxidative damage in human liver cells through Nrf-2 Signaling pathway","volume":"12","author":"Yang","year":"2024","journal-title":"Toxics"},{"key":"2025100914524545200_ref13","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from mendelian randomization using the MR-egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"2025100914524545200_ref14","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"2025100914524545200_ref15","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J Comput Chem"},{"key":"2025100914524545200_ref16","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: multiple ligand-protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J Chem Inf Model"},{"key":"2025100914524545200_ref17","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1007\/s10822-010-9352-6","article-title":"Ligand docking and binding site analysis with PyMOL and Autodock\/Vina","volume":"24","author":"Seeliger","year":"2010","journal-title":"J Comput Aided Mol Des"},{"key":"2025100914524545200_ref18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1-2","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"2025100914524545200_ref19","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"V\u00f5sa","year":"2021","journal-title":"Nat Genet"},{"key":"2025100914524545200_ref20","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.envres.2018.12.043","article-title":"Environmental pyrethroid exposure and diabetes in U.S. adults","volume":"172","author":"Park","year":"2019","journal-title":"Environ Res"},{"key":"2025100914524545200_ref21","doi-asserted-by":"publisher","first-page":"12005","DOI":"10.3390\/ijerph182212005","article-title":"Environmental pyrethroid exposure and cognitive dysfunction in U.S. older adults: the NHANES 2001-2002","volume":"18","author":"Kim","year":"2021","journal-title":"Int J Environ Res Public Health"},{"key":"2025100914524545200_ref22","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1007\/s00774-024-01499-2","article-title":"Associations of pyrethroid exposure with bone mineral density and osteopenia in adults","volume":"42","author":"Shen","year":"2024","journal-title":"J Bone Miner Metab"},{"key":"2025100914524545200_ref23","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1080\/15563650.2023.2268981","article-title":"2022 annual report of the National Poison Data System (NPDS) from America's poison Centers: 40th annual report","volume":"61","author":"Gummin","year":"2023","journal-title":"Clin Toxicol"},{"key":"2025100914524545200_ref24","doi-asserted-by":"publisher","first-page":"115992","DOI":"10.1016\/j.bmc.2020.115992","article-title":"A network pharmacology-integrated metabolomics strategy for clarifying the action mechanisms of Schisandrae chinensis fructus for treating drug-induced liver injury by acetaminophen","volume":"31","author":"Li","year":"2021","journal-title":"Bioorg Med Chem"},{"key":"2025100914524545200_ref25","doi-asserted-by":"publisher","first-page":"355","DOI":"10.3760\/CMA.J.ISSN.0254-1416.2015.03.024","article-title":"Role of Src kinase in liver injury in endotoxemic mice","volume":"35","author":"Duan","year":"2015","journal-title":"Chinese Journal of Anesthesiology"},{"key":"2025100914524545200_ref26","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1007\/s00204-016-1864-y","article-title":"Oxidative stress and gene expression profiling of cell death pathways in alpha-cypermethrin-treated SH-SY5Y cells","volume":"91","author":"Romero","year":"2017","journal-title":"Arch Toxicol"},{"key":"2025100914524545200_ref27","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.1039\/d5fo00656b","article-title":"Hepatoprotective effects of wine-steamed schisandra sphenanthera fruit in alleviating APAP-induced liver injury via the gut-liver axis","volume":"16","author":"Wang","year":"2025","journal-title":"Food Funct"},{"key":"2025100914524545200_ref28","doi-asserted-by":"publisher","first-page":"104792","DOI":"10.1016\/j.tiv.2020.104792","article-title":"Bifenthrin insecticide promotes oxidative stress and increases inflammatory mediators in human neuroblastoma cells through NF-kappaB pathway","volume":"65","author":"Gargouri","year":"2020","journal-title":"Toxicol In Vitro"},{"key":"2025100914524545200_ref29","doi-asserted-by":"publisher","first-page":"103784","DOI":"10.1016\/j.etap.2021.103784","article-title":"Cis-bifenthrin inhibits cortisol and aldosterone biosynthesis in human adrenocortical H295R cells via cAMP signaling cascade","volume":"89","author":"Yang","year":"2022","journal-title":"Environ Toxicol Pharmacol"},{"key":"2025100914524545200_ref30","doi-asserted-by":"publisher","first-page":"167266","DOI":"10.1016\/j.bbadis.2024.167266","article-title":"Gpbar-1\/cAMP\/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome","volume":"1870","author":"Zhuang","year":"2024","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2025100914524545200_ref31","doi-asserted-by":"publisher","first-page":"3936","DOI":"10.1002\/fsn3.1709","article-title":"Mallotus furetianus extract protects against ethanol-induced liver injury via the activation of the cAMP-PKA pathway","volume":"8","author":"Yoshikawa","year":"2020","journal-title":"Food Sci Nutr"},{"key":"2025100914524545200_ref32","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signalling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2025100914524545200_ref33","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.3892\/ijo.2016.3373","article-title":"Scrophularia orientalis extract induces calcium signaling and apoptosis in neuroblastoma cells","volume":"48","author":"Lange","year":"2016","journal-title":"Int J Oncol"},{"key":"2025100914524545200_ref34","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.mito.2021.03.010","article-title":"Mitochondrial calcium signaling in the brain and its modulation by neurotropic viruses","volume":"59","author":"Chaudhuri","year":"2021","journal-title":"Mitochondrion"},{"key":"2025100914524545200_ref35","doi-asserted-by":"publisher","first-page":"173097","DOI":"10.1016\/j.scitotenv.2024.173097","article-title":"Beta-cyfluthrin impairs implantation process by inducing mitochondrial defects and changes in reactive oxygen species-mediated signaling pathways in porcine trophectoderm and uterine luminal epithelial cells","volume":"934","author":"Park","year":"2024","journal-title":"Sci Total Environ"},{"key":"2025100914524545200_ref36","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR signaling transduction pathway and targeted therapies in cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol Cancer"},{"key":"2025100914524545200_ref37","doi-asserted-by":"publisher","first-page":"4349","DOI":"10.3390\/nu15204349","article-title":"Eriodictyol alleviated LPS\/D-GalN-induced acute liver injury by inhibiting oxidative stress and cell apoptosis via PI3K\/AKT Signaling pathway","volume":"15","author":"Zheng","year":"2023","journal-title":"Nutrients"},{"key":"2025100914524545200_ref38","doi-asserted-by":"publisher","first-page":"110375","DOI":"10.1016\/j.intimp.2023.110375","article-title":"Leonurine alleviates acetaminophen-induced acute liver injury by regulating the PI3K\/AKT signaling pathway in mice","volume":"120","author":"Yu","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"2025100914524545200_ref39","doi-asserted-by":"publisher","first-page":"102733","DOI":"10.1016\/j.tice.2025.102733","article-title":"Regulation of TGF-\u03b21, PI3K\/PIP3\/Akt, Nrf-2\/Keap-1 and NF-\u03baB signaling pathways to avert bifenthrin induced hepatic injury: a palliative role of daidzein","volume":"93","author":"El Safadi","year":"2025","journal-title":"Tissue Cell"},{"key":"2025100914524545200_ref40","doi-asserted-by":"publisher","first-page":"62975","DOI":"10.1007\/s11356-021-15190-w","article-title":"Protective effects of rutin against deltamethrin-induced hepatotoxicity and nephrotoxicity in rats via regulation of oxidative stress, inflammation, and apoptosis","volume":"28","author":"K\u00fc\u00e7\u00fckler","year":"2021","journal-title":"Environ Sci Pollut Res Int"},{"key":"2025100914524545200_ref41","doi-asserted-by":"publisher","first-page":"109268","DOI":"10.1016\/j.intimp.2022.109268","article-title":"Nilotinib alleviated acetaminophen-induced acute hepatic injury in mice through inhibiting HIF-1alpha\/VEGF-signaling pathway","volume":"112","author":"Menisy","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"2025100914524545200_ref42","doi-asserted-by":"publisher","first-page":"G764","DOI":"10.1152\/ajpgi.90622.2008","article-title":"cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 beta\/alpha in rat hepatocytes","volume":"296","author":"Gates","year":"2009","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2025100914524545200_ref43","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1161\/CIRCRESAHA.117.310183","article-title":"PI3K and calcium Signaling in cardiovascular disease","volume":"121","author":"Ghigo","year":"2017","journal-title":"Circ Res"},{"key":"2025100914524545200_ref44","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1007\/s00204-007-0201-x","article-title":"VEGF isoforms and receptors expression throughout acute acetaminophen-induced liver injury and regeneration","volume":"81","author":"Papastefanou","year":"2007","journal-title":"Arch Toxicol"},{"key":"2025100914524545200_ref45","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1093\/rheumatology\/key261","article-title":"PIM-1 kinase is a novel regulator of proinflammatory cytokine-mediated responses in rheumatoid arthritis fibroblast-like synoviocytes","volume":"58","author":"Ha","year":"2019","journal-title":"Rheumatology"},{"key":"2025100914524545200_ref46","doi-asserted-by":"publisher","first-page":"104877","DOI":"10.1016\/j.bioorg.2021.104877","article-title":"Synthesis of new substituted pyridine derivatives as potent anti-liver cancer agents through apoptosis induction: In vitro, in vivo, and in silico integrated approaches","volume":"111","author":"Boraei","year":"2021","journal-title":"Bioorg Chem"},{"key":"2025100914524545200_ref47","doi-asserted-by":"publisher","first-page":"122714","DOI":"10.1016\/j.lfs.2024.122714","article-title":"PIM1 alleviated liver oxidative stress and NAFLD by regulating the NRF2\/HO-1\/NQO1 pathway","volume":"349","author":"Yang","year":"2024","journal-title":"Life Sci"},{"key":"2025100914524545200_ref48","doi-asserted-by":"publisher","first-page":"104938","DOI":"10.1016\/j.pestbp.2021.104938","article-title":"Mitochondrial dysfunction and oxidative stress in liver of male albino rats after exposing to sub-chronic intoxication of chlorpyrifos, cypermethrin, and imidacloprid","volume":"178","author":"Taha","year":"2021","journal-title":"Pestic Biochem Physiol"},{"key":"2025100914524545200_ref49","doi-asserted-by":"publisher","first-page":"116817","DOI":"10.1016\/j.taap.2024.116817","article-title":"d-tetramethrin causes zebrafish hepatotoxicity by inducing oxidative stress and inhibiting cell proliferation","volume":"483","author":"Li","year":"2024","journal-title":"Toxicol Appl Pharmacol"},{"key":"2025100914524545200_ref50","doi-asserted-by":"publisher","first-page":"e2411719","DOI":"10.1002\/advs.202411719","article-title":"Targeting FDFT1 reduces cholesterol and bile acid production and delays hepatocellular carcinoma progression through the HNF4A\/ALDOB\/AKT1 Axis","volume":"12","author":"Cai","year":"2025","journal-title":"Advanced science"},{"key":"2025100914524545200_ref51","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.1002\/cam4.4716","article-title":"Identification of FDFT1 as a potential biomarker associated with ferroptosis in ccRCC","volume":"11","author":"Huang","year":"2022","journal-title":"Cancer Med"}],"container-title":["Toxicology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/14\/5\/tfaf143\/64602103\/tfaf143.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/14\/5\/tfaf143\/64602103\/tfaf143.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:52:54Z","timestamp":1760035974000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxres\/article\/doi\/10.1093\/toxres\/tfaf143\/8280150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,7]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,9,7]]}},"URL":"https:\/\/doi.org\/10.1093\/toxres\/tfaf143","relation":{},"ISSN":["2045-4538"],"issn-type":[{"value":"2045-4538","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,7]]},"article-number":"tfaf143"}}