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Although increasing evidence suggests that plasticizers may disrupt gastrointestinal homeostasis, their potential molecular links with inflammatory gastrointestinal disorders (IGDs) remain unclear. Methods: This study aimed to systematically identify potential molecular targets and pathways linking representative plasticizers with IGDs. An integrative network toxicology framework was applied to investigate four plasticizers, including dimethyl phthalate (DMP), diethyl phthalate (DEP), dioctyl phthalate\/di(2-ethylhexyl) phthalate (DOP\/DEHP), and acetyl tributyl citrate (ATBC), in relation to Crohn\u2019s disease (CD), ulcerative colitis (UC), esophagitis, and gastritis. Plasticizer- and disease-related targets were collected from public databases, followed by overlapping target screening, protein\u2013protein interaction network analysis, functional enrichment analysis, GEO-based transcriptomic validation, molecular docking, molecular dynamics simulation, and single-cell RNA-seq analysis. Results: Disease-specific candidate targets were identified, including CXCL8 and FN1 for CD, IL1B for UC, MAPK3, FASN, FN1, PPARG, CXCL8, FOS, and HIF1A for esophagitis, and MMP9, TNF, TLR4, IL6, CCR2, IFNG, and PTGS2 for gastritis. Cross-disease analysis further identified plasticizer-associated signature targets, including MMP7 for DMP, HMOX1 and NOS2 for DEP, and LTF and CCL11 for ATBC. Enrichment analysis indicated that these targets were mainly involved in inflammatory, chemokine, MAPK-related, and xenobiotic response pathways. Molecular docking and dynamics simulations suggested stable interactions between selected plasticizers and candidate targets, while single-cell analysis revealed their cell-type-specific expression patterns in epithelial, immune, and stromal compartments. Conclusions: This study provides an exploratory network toxicology framework for identifying potential molecular associations between plasticizer exposure and IGDs. The findings highlight disease-specific and plasticizer-associated candidate targets that may guide future experimental validation and environmental risk assessment.<\/jats:p>","DOI":"10.3390\/genes17060667","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:43:02Z","timestamp":1780904582000},"page":"667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Network Toxicology Reveals Potential Molecular Targets Linking Plasticizer Exposure to Inflammatory Gastrointestinal Disorders"],"prefix":"10.3390","volume":"17","author":[{"given":"Yongqi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China"},{"name":"Department of Immunology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ruan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghan","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaohan","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luojin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5249-002X","authenticated-orcid":false,"given":"Mengmeng","family":"Sang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, Nantong 226001, China"},{"name":"Basic Medical Research Center, School of Medicine, Nantong University, Nantong 226019, China"},{"name":"Jiangsu Province Key Laboratory in University for Inflammation and Molecular Drug Target, Nantong University, Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-820X","authenticated-orcid":false,"given":"Liming","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, Nantong 226001, China"},{"name":"Basic Medical Research Center, School of Medicine, Nantong University, Nantong 226019, China"},{"name":"Jiangsu Province Key Laboratory in University for Inflammation and Molecular Drug Target, Nantong University, Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jhazmat.2017.10.014","article-title":"An overview of chemical additives present in plastics: Migration, release, fate and environmental impact during their use, disposal and recycling","volume":"344","author":"Hahladakis","year":"2018","journal-title":"J. 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