{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:21:14Z","timestamp":1787822474830,"version":"build-2784847793"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Aging is a major risk factor for atherosclerosis (AS), but the aging\u2010associated molecular characteristics and immune heterogeneity of AS remain incompletely understood. This study aimed to identify aging\u2010related hub genes and characterize immune landscapes across aging subtypes of AS using integrated bioinformatics and experimental validation. AS\u2010related candidate genes were found by overlapping DEGs identified by limma and key module genes identified by Weighted Correlation Network Analysis (WGCNA) based on the GSE100927 dataset. Consensus clustering based on aging\u2010related DEGs (differential expression analysis based on 125 aging\u2010related genes between AS and control) was performed to identify aging subtypes and characterize immune landscapes. Typical genes were picked out using four machine learning models: Support Vector Machine (SVM), Random Forest (RF), eXtreme Gradient Boosting (XGB), and Generalized Linear Model (GLM). The expression of central genes was verified through single\u2014cell data analysis. Patients with AS were enrolled (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930), and atherosclerotic plaque and adjacent normal arterial tissues were collected. Quantitative Polymerase Chain Reaction (qPCR) validation was performed in atherosclerotic plaques and oxidized Low\u2010Density Lipoprotein (ox\u2010LDL)\u2010treated THP\u20101 macrophage. The effect of crucial genes on ox\u2010LDL\u2010induced THP\u20101 macrophage inflammatory response and foaming were validated by qPCR, ELISA and Oil Red O Staining. We identified 76 aging\u2010related DEGs and classified AS samples into two aging\u2010related subtypes (C1 and C2) with distinct immune infiltration characteristics. Machine learning analysis based on 43 candidate genes identified 5 hub genes: heat shock protein family B (small) member 7 (HSPB7), myelin expression factor 2 (MYEF2), dual specificity phosphatase 26 (DUSP26), tandem C2 domains, nuclear (TC2N), and phospholamban (PLN), whose expression patterns were further validated by single\u2010cell RNA sequencing. Moreover, TC2N and PLN were significantly downregulated in atherosclerotic plaque tissues. TC2N and PLN expressions in atherosclerotic plaque tissue of AS patient were significantly reduced. TC2N was significantly decreased in ox\u2010LDL\u2010treated THP\u20101 macrophage. TC2N overexpression alleviated ox\u2010LDL\u2010induced THP\u20101 macrophage inflammatory response but also alleviated cell foaming. This integrated bioinformatics and experimental study identified five hub genes (HSPB7, MYEF2, DUSP26, TC2N, and PLN) associated with AS. Experimental validation confirmed that TC2N is significantly downregulated in human atherosclerotic plaques and ox\u2010LDL\u2010treated THP\u20101 macrophages, TC2N overexpression alleviates inflammatory responses and foam cell formation. These findings provide insights into the molecular mechanisms linking aging and immune dysregulation in AS and highlight TC2N as a potential regulator of AS progression.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70382","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:32:15Z","timestamp":1787819535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Hub Gene Characteristics and Immune Landscapes Across Aging Subtypes in Atherosclerosis: A Machine Learning\u2010Based Multi\u2010Omics Study With Experimental Verification"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6464-6576","authenticated-orcid":false,"given":"Qiyu","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Nantong Hospital of Traditional Chinese Medicine Nantong Hospital Affiliated to Nanjing University of Chinese Medicine  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center  Wuxi Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jibin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cancer Research Center Tumor Hospital Affiliated to Nantong University, Medical School of Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Diao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory West China Hospital Sichuan University Jintang Hospital, Jintang First People's Hospital  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuopeng","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of General Surgery Nanjing Luhe People's Hospital  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Nantong Hospital of Traditional Chinese Medicine Nantong Hospital Affiliated to Nanjing University of Chinese Medicine  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9690-2104","authenticated-orcid":false,"given":"Haixia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cancer Research Center Tumor Hospital Affiliated to Nantong University, Medical School of Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"1","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbadis.2025.168060","article-title":"The Aging Interactome: From Cellular Dysregulation to Therapeutic Frontiers in Age\u2010Related Diseases","volume":"1872","author":"Abo Qoura L.","year":"2026","journal-title":"Biochimica et Biophysica Acta, Molecular Basis of Disease"},{"key":"e_1_2_13_3_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.arr.2024.102273","article-title":"Understanding the Intricacies of Cellular Senescence in Atherosclerosis: Mechanisms and Therapeutic Implications","volume":"96","author":"Ali I.","year":"2024","journal-title":"Ageing Research Reviews"},{"issue":"1","key":"e_1_2_13_4_1","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/s42003-022-04056-7","article-title":"Decoding the Transcriptome of Calcified Atherosclerotic Plaque at Single\u2010Cell Resolution","volume":"5","author":"Alsaigh T.","year":"2022","journal-title":"Communications Biology"},{"issue":"1","key":"e_1_2_13_5_1","first-page":"D28","article-title":"China National Center for Bioinformation in 2026","volume":"54","author":"Database Resources of the National Genomics Data Center","year":"2026","journal-title":"Nucleic Acids Research"},{"issue":"1","key":"e_1_2_13_6_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00011-023-01817-w","article-title":"Unveiling the Role of ABI3 and Hub Senescence\u2010Related Genes in Macrophage Senescence for Atherosclerotic Plaque Progression","volume":"73","author":"Fu Y.","year":"2024","journal-title":"Inflammation Research: Official Journal of the European Histamine Research Society [Et al]"},{"issue":"7","key":"e_1_2_13_7_1","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/s41418-018-0202-8","article-title":"TC2N, a Novel Oncogene, Accelerates Tumor Progression by Suppressing p53 Signaling Pathway in Lung Cancer","volume":"26","author":"Hao X. 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Y.","year":"2025","journal-title":"Cellular & Molecular Biology Letters"},{"issue":"19","key":"e_1_2_13_34_1","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1016\/j.jacc.2018.08.2161","article-title":"Long Noncoding RNAs in Atherosclerosis: JACC Review Topic of the Week","volume":"72","author":"Zhang Z.","year":"2018","journal-title":"Journal of the American College of Cardiology"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70382","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cbdd.70382","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70382","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:55:18Z","timestamp":1787820918000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.70382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/cbdd.70382"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.70382","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"value":"1747-0277","type":"print"},{"value":"1747-0285","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70382"}}