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Macrophages play a central role by forming foam cells and secreting pro-atherogenic cytokines, such as TNF-\u03b1, IFN-\u03b3, and IL-1\u03b2, which destabilize atherosclerotic plaques, expanding the lipid core and increasing the risk of thrombosis and ischemia. Despite the significant health burden of subclinical atherosclerosis, few targeted therapies exist. Current treatments, including monoclonal antibodies, are limited by high costs and immunosuppressive side effects, underscoring the urgent need for alternative therapeutic strategies. In this study, we employed in silico drug repositioning to identify multitarget inhibitors against TNF-\u03b1, IFN-\u03b3, and IL-1\u03b2, leveraging a virtual screening of 2750 FDA-approved drugs followed by molecular dynamics simulations to assess the stability of selected cytokine\u2013ligand complexes. This computational approach provides structural insights into potential inhibitors. Additionally, we highlight nutraceutical options, such as fatty acids (oleic, linoleic and eicosapentaenoic acid), which exhibited strong and stable interactions with key cytokine targets. Our study suggests that these bioactive compounds could serve as effective new therapeutic approaches for atherosclerosis.<\/jats:p>","DOI":"10.3390\/ijms26072931","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T07:46:50Z","timestamp":1742802410000},"page":"2931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Virtual Screening and Molecular Dynamics of Cytokine\u2013Drug Complexes for Atherosclerosis Therapy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7969-9439","authenticated-orcid":false,"given":"Mar\u00eda Ang\u00e9lica","family":"Rodr\u00edguez-Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Posgrado de Ingenier\u00eda Bioqu\u00edmica, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT de Celaya, Celaya 38010, Guanajuato, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola 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