{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:33Z","timestamp":1785422733774,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the \u201cWestern Young Scholars\u201d Program of the Chinese Academy of Sciences"},{"name":"the Ningxia Autonomous Region Youth Leading Talent Project in 2023"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82560099"],"award-info":[{"award-number":["82560099"]}],"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":["82271626"],"award-info":[{"award-number":["82271626"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82560099"],"award-info":[{"award-number":["82560099"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82271626"],"award-info":[{"award-number":["82271626"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004772","name":"Ningxia Natural Science Foundation","doi-asserted-by":"publisher","award":["2022AAC05025"],"award-info":[{"award-number":["2022AAC05025"]}],"id":[{"id":"10.13039\/501100004772","id-type":"DOI","asserted-by":"publisher"}]},{"name":"2026 Undergraduate Innovation and Entrepreneurship Project","award":["NYCXCYX009"],"award-info":[{"award-number":["NYCXCYX009"]}]},{"name":"2026 Undergraduate Innovation and Entrepreneurship Project","award":["NYCXCYX010"],"award-info":[{"award-number":["NYCXCYX010"]}]},{"name":"the open competition mechanism to select the best candidates for key research projects of Ningxia Medical University","award":["XJKF230106"],"award-info":[{"award-number":["XJKF230106"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study integrates multidimensional computational approaches\u2014network toxicology, machine learning, molecular docking, and molecular dynamics simulation\u2014to systematically elucidate the toxic mechanism by which the environmental pollutant diisononyl cyclohexane-1,2-dicarboxylate (DINCH) contributes to atherosclerosis. By jointly mining multiple databases, we obtained 246 targets common to DINCH and atherosclerosis. LASSO regression and support vector machine\u2013recursive feature elimination (SVM-RFE) then identified 8 significantly upregulated core targets (CSF1R, CD36, CCL3, CCR2, ADAM8, TLR1, CTSS, and MMP1). Functional enrichment analysis showed that these core targets were significantly associated with key signaling pathways, including lipid and atherosclerosis, the PPAR signaling pathway, the PI3K\u2013Akt signaling pathway, and the AGE\u2013RAGE signaling pathway in diabetic complications. Differential gene analysis confirmed that these genes were significantly upregulated in diseased tissues, and receiver operating characteristic (ROC) analysis demonstrated excellent diagnostic performance (AUC = 0.87\u20130.96). Immune cell infiltration analysis further revealed a strong association between the core targets and immune cell populations, notably macrophages and T cells. Molecular docking and molecular dynamics simulations showed that DINCH had high affinity for the core targets, and its binding to CCR2 was the most stable (binding free energy = \u22127.6 kcal\/mol). The final AOP framework systematically presented the cascade by which DINCH may contribute to atherosclerosis through metabolic disruption and immune activation. This study provides new mechanistic insights into the development of DINCH-induced atherosclerosis and offers a theoretical basis for health risk assessment of environmental pollutants.<\/jats:p>","DOI":"10.3390\/ijms27114668","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:14:52Z","timestamp":1779452092000},"page":"4668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Toxicological Relationship Between Diisononyl Cyclohexane-1,2-dicarboxylate and Atherosclerosis Through Network Toxicology, Machine Learning, and Multi-Dimensional Bioinformatics"],"prefix":"10.3390","volume":"27","author":[{"given":"Jingbo","family":"Cao","sequence":"first","affiliation":[{"name":"General Hospital of Ningxia Medical University, School of Public Health, Ningxia Medical University, Yinchuan 750004, China"},{"name":"The Second School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyao","family":"Yang","sequence":"additional","affiliation":[{"name":"General Hospital of Ningxia Medical University, School of Public Health, Ningxia Medical University, Yinchuan 750004, China"},{"name":"The Second School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"General Hospital of Ningxia Medical University, School of Public Health, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwei","family":"Zou","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huning","family":"Zhang","sequence":"additional","affiliation":[{"name":"General Hospital of Ningxia Medical University, School of Public Health, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0606-5937","authenticated-orcid":false,"given":"Anning","family":"Yang","sequence":"additional","affiliation":[{"name":"General Hospital of Ningxia Medical University, School of Public Health, Ningxia Medical University, Yinchuan 750004, China"},{"name":"NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-0811","authenticated-orcid":false,"given":"Yue","family":"Sun","sequence":"additional","affiliation":[{"name":"General Hospital of Ningxia Medical University, School of Public Health, Ningxia Medical University, Yinchuan 750004, China"},{"name":"NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China"},{"name":"Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","article-title":"Atherosclerosis","volume":"5","author":"Libby","year":"2019","journal-title":"Nat. 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