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However, the role of endothelial Matrin\u20103 in atherosclerosis has not been previously studied. Here, we found that Matrin\u20103 silencing induces endothelial senescence, characterized by reduced cell proliferation, increased senescence\u2010associated \u03b2\u2010galactosidase activity, and impaired mitochondrial function in\u00a0vitro. Quantitative proteomics and bulk RNA\u2010sequencing identified hundreds of differentially expressed genes and proteins in human endothelial cells. Bioinformatic analyses revealed enrichment of pathways related to DNA replication, p53 signaling, cell\u2010cycle regulation, and cellular senescence. To examine the role of endothelial Matrin\u20103 in atherosclerosis, we generated Matrin\u20103 floxed mice on a low\u2010density lipoprotein receptor\u2010knockout background and crossed them with mice carrying an endothelial cell\u2010specific, tamoxifen\u2010inducible Cre driver. In a mouse model of atherosclerosis, endothelial cell\u2010specific Matrin\u20103 deficiency increased atherosclerotic lesion area by 1.41\u2010fold and was associated with increased plasma low\u2010density lipoprotein cholesterol and triglycerides, increased hepatic cholesterol and triglycerides, and substantial transcriptional alterations in the aortic intima. Endothelial Matrin\u20103 deficiency also induced hepatic steatosis, fibrosis, inflammation, and endothelial senescence. Single\u2010nucleus RNA\u2010sequencing of the liver further revealed transcriptional reprogramming of hepatocytes, including alterations in pathways related to lipid metabolism, inflammation, and constitutive androstane receptor signaling, consistent with a functional link between endothelial Matrin\u20103 deficiency and hepatocyte transcriptional responses. Finally, Matrin\u20103 expression was reduced in mouse and human atherosclerotic plaques. Together, these findings identify endothelial Matrin\u20103 as an important regulator of endothelial senescence and lipid homeostasis and demonstrate that endothelial Matrin\u20103 deficiency is associated with both local vascular alterations and systemic metabolic dysfunction in atherosclerosis.<\/jats:p>","DOI":"10.1096\/fj.202602809rr","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T11:36:12Z","timestamp":1792236972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial Matrin\u20103 Limits Cellular Senescence and Lipid Dysregulation to Protect Against Murine Atherosclerosis"],"prefix":"10.1096","volume":"40","author":[{"given":"Xiao","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Biochemistry University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatema Yeasmin","family":"Tanni","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachelle Nelson","family":"Zoni","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Abdollahi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Childs","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1156-0375","authenticated-orcid":false,"given":"Xinghui","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"},{"name":"Nebraska Center for the Prevention of Obesity Diseases Through Dietary Molecules University of Nebraska\u2010Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26031364"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-024-01037-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.09.012"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242417129"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000013836.85741.17"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6659"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy007"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz919"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-94097-5"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00739-0"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242015160"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2023.01.008"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10846"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4172"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.11.026"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000203526.75772.4b"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000134530.27208.41"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.731958"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11162494"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3688"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00326"},{"key":"e_1_2_10_23_1","first-page":"326","article-title":"Low Expression of MATR3 Is Associated With Poor Survival in Clear Cell Renal Cell Carcinoma","volume":"11","author":"Durslewicz J.","year":"2023","journal-title":"Biomedicine"},{"key":"e_1_2_10_24_1","article-title":"Matrin3 (MATR3) Expression Is Associated With Hemophagocytosis","volume":"10","author":"Yang W. 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