{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:04:56Z","timestamp":1779433496495,"version":"3.53.1"},"reference-count":50,"publisher":"Frontiers Media SA","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\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cellular senescence contributes to atherosclerotic plaque progression and instability, yet senescence-related diagnostic biomarkers and actionable targets remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To identify senescence-related diagnostic\/therapeutic targets in atherosclerosis using integrative systems biology, and to prioritize natural products that modulate the lead target with experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic profiles from GSE21545 (126 carotid plaques and 97 paired peripheral blood mononuclear cell samples) were analyzed to identify differentially expressed genes and intersected with CellAge senescence genes. WGCNA and two machine-learning approaches (LASSO and SVM-RFE) were used for feature selection and target prioritization, followed by ROC analysis, functional enrichment, immune infiltration analysis, and PPI network construction. A natural product library (5,565 compounds) was screened against SIRT1 via hierarchical docking, MM-GBSA rescoring, and 100-ns molecular dynamics simulations. Lead compound activity was tested in H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      -injured HUVECs using CCK-8 assays, qRT-PCR, Western blotting, and siRNA knockdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 255 senescence-related differentially expressed genes enriched in oxidative stress and inflammatory pathways. WGCNA and machine learning converged on 10 hub genes, with SIRT1 prioritized based on network centrality and diagnostic performance (AUC = 0.997, 95% CI: 0.992\u20131.000) and reduced expression in plaque samples. Virtual screening nominated Poliumoside as a high-affinity SIRT1 binder with stable binding dynamics in molecular simulations. In HUVECs, Poliumoside (40\u00a0\u03bcM) mitigated H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      -induced injury and activated the SIRT1\/NRF2\/HO-1 axis; these effects were attenuated by SIRT1 knockdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study highlights SIRT1 as a senescence-related theranostic candidate in atherosclerosis and identifies Poliumoside as a natural SIRT1 activator with endothelial protective activity\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1805938","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:08:20Z","timestamp":1779430100000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative systems biology identifies SIRT1 as a senescence-related theranostic target in atherosclerosis and poliumoside as a natural activator"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaolong","family":"Wang","sequence":"first","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]},{"name":"Department of Pharmacy, Ningxia Chinese Medicine Research Center","place":["Yinchuan, Ningxia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runlu","family":"Shi","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Ji","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwen","family":"Jia","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tian","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Ningxia Chinese Medicine Research Center","place":["Yinchuan, Ningxia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao-Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]},{"name":"Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3390\/brainsci13020175","article-title":"Parkinson's disease gene biomarkers screened by the LASSO and SVM algorithms","volume":"13","author":"Bao","year":"2023","journal-title":"Brain Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: archive for functional genomics data sets-update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cmet.2016.05.011","article-title":"Metformin as a tool to target aging","volume":"23","author":"Barzilai","year":"2016","journal-title":"Cell Metab."},{"key":"B5","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12860-022-00435-4","article-title":"Angiogenic ability of human endothelial cells was decreased following senescence induction with hydrogen peroxide: possible role of vegfr-2\/akt-1 signaling pathway","volume":"23","author":"Berenjabad","year":"2022","journal-title":"BMC Mol. Cell Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.fct.2013.07.021","article-title":"Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases","volume":"61","author":"Carrizzo","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1038\/nm.4000","article-title":"Cellular senescence in aging and age-related disease: from mechanisms to therapy","volume":"21","author":"Childs","year":"2015","journal-title":"Nat. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1126\/science.aaf6659","article-title":"Senescent intimal foam cells are deleterious at all stages of atherosclerosis","volume":"354","author":"Childs","year":"2016","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1016\/S0140-6736(10)61350-5","article-title":"Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials","volume":"376","author":"Cholesterol Treatment Trialists","year":"2010","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.pharmthera.2018.03.004","article-title":"Sirtuin activators and inhibitors: promises, achievements, and challenges","volume":"188","author":"Dai","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"111913","DOI":"10.1016\/j.mce.2023.111913","article-title":"Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy","author":"Ding","year":"2023","journal-title":"Mol. Cell Endocrinol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1016\/j.bbagen.2017.03.017","article-title":"Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats","volume":"1861","author":"Feng","year":"2017","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.7150\/thno.30787","article-title":"Berberine in cardiovascular and metabolic diseases: from mechanisms to therapeutics","volume":"9","author":"Feng","year":"2019","journal-title":"Theranostics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"156881","DOI":"10.1016\/j.phymed.2025.156881","article-title":"Poliumoside alleviates microglia-mediated inflammation and blood-brain barrier disruption via modulating the polarization of microglia after ischemic stroke in mice","volume":"143","author":"Gao","year":"2025","journal-title":"Phytomedicine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nrneph.2017.51","article-title":"The immunology of atherosclerosis","volume":"13","author":"Gistera","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1007\/s11357-022-00625-0","article-title":"Unbiased proteomic analysis of extracellular vesicles secreted by senescent human vascular smooth muscle cells reveals their ability to modulate immune cell functions","volume":"44","author":"G\u0142uchowska","year":"2022","journal-title":"Geroscience"},{"key":"B18","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1161\/CIRCULATIONAHA.112.124404","article-title":"Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis","volume":"127","author":"Gorenne","year":"2013","journal-title":"Circulation"},{"key":"B19","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1093\/cvr\/cvy007","article-title":"Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis","volume":"114","author":"Grootaert","year":"2018","journal-title":"Cardiovasc Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1082","DOI":"10.1161\/CIR.0000000000000625","article-title":"2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA guideline on the management of blood cholesterol: a report of the American college of cardiology\/american heart association task force on clinical practice guidelines","volume":"139","author":"Grundy","year":"2019","journal-title":"Circulation"},{"key":"B21","doi-asserted-by":"publisher","first-page":"137463","DOI":"10.1016\/j.ijbiomac.2024.137463","article-title":"Design strategies of polysaccharide, protein and lipid-based nano-delivery systems in improving the bioavailability of polyphenols and regulating gut homeostasis","volume":"283","author":"Guo","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/nrd4510","article-title":"The re-emergence of natural products for drug discovery in the genomics era","volume":"14","author":"Harvey","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"B23","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/nature01960","article-title":"Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan","volume":"425","author":"Howitz","year":"2003","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"16017","DOI":"10.1038\/npjamd.2016.17","article-title":"It takes two to tango: NAD(+) and sirtuins in aging\/longevity control","volume":"2","author":"Imai","year":"2016","journal-title":"NPJ Aging Mech. Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1016\/j.bbadis.2018.08.008","article-title":"Endothelial cell senescence in aging-related vascular dysfunction","volume":"1865","author":"Jia","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.3390\/life11121323","article-title":"Linking In vitro models of endothelial dysfunction with cell senescence","volume":"11","author":"Jimenez Trinidad","year":"2021","journal-title":"Life (Basel)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nature11861","article-title":"mTOR is a key modulator of ageing and age-related disease","volume":"493","author":"Johnson","year":"2013","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"331","DOI":"10.3390\/biomedicines14020331","article-title":"The role of cellular senescence and SASP in the pathogenesis of atherosclerosis and the therapeutic potential of senolytic strategies in cardiovascular diseases","volume":"14","author":"Krupa","year":"2026","journal-title":"Biomedicines"},{"key":"B29","doi-asserted-by":"publisher","first-page":"20049","DOI":"10.1038\/s41598-019-56635-0","article-title":"Distinct role of sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) in inhibiting cargo-loading and release of extracellular vesicles","volume":"9","author":"Lee","year":"2019","journal-title":"Sci. Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/nature10146","article-title":"Progress and challenges in translating the biology of atherosclerosis","volume":"473","author":"Libby","year":"2011","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Lopez-Otin","year":"2013","journal-title":"Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.1016\/j.jacc.2019.10.009","article-title":"The global burden of cardiovascular diseases and risk factors: 2020 and beyond","volume":"74","author":"Mensah","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"B35","doi-asserted-by":"publisher","first-page":"109953","DOI":"10.1016\/j.abb.2024.109953","article-title":"Network of extracellular vesicles surrounding senescent cells","volume":"754","author":"Okawa","year":"2024","journal-title":"Arch. Biochem. Biophys."},{"key":"B36","doi-asserted-by":"publisher","first-page":"4331","DOI":"10.3390\/ijms20184331","article-title":"Molecular docking: shifting paradigms in drug discovery","volume":"20","author":"Pinzi","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.cmet.2018.02.011","article-title":"Therapeutic potential of NAD-boosting molecules: the in Vivo evidence","volume":"27","author":"Rajman","year":"2018","journal-title":"Cell Metab."},{"key":"B38","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1111\/acel.12458","article-title":"Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice","volume":"15","author":"Roos","year":"2016","journal-title":"Aging Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1161\/CIRCRESAHA.117.311147","article-title":"New insights into the role of mTOR signaling in the cardiovascular system","volume":"122","author":"Sciarretta","year":"2018","journal-title":"Circ. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s40779-023-00498-0","article-title":"Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: the risk of senescent drift induction in secretome-based therapeutics","volume":"10","author":"Smirnova","year":"2023","journal-title":"Mil. Med. Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"640","DOI":"10.4161\/cc.10.4.14863","article-title":"Protective roles of SIRT1 in atherosclerosis","volume":"10","author":"Stein","year":"2011","journal-title":"Cell Cycle"},{"key":"B42","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41569-020-0431-7","article-title":"Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6","volume":"18","author":"Tyrrell","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/s41573-019-0024-5","article-title":"Applications of machine learning in drug discovery and development","volume":"18","author":"Vamathevan","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3578","DOI":"10.3390\/nu15163578","article-title":"Natural phytochemicals as SIRT activators-focus on potential biochemical mechanisms","volume":"15","author":"Wici\u0144ski","year":"2023","journal-title":"Nutrients"},{"key":"B45","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1146\/annurev-food-060721-023817","article-title":"Bioavailability of food polyphenols: current state of knowledge","volume":"16","author":"Williamson","year":"2025","journal-title":"Annu. Rev. Food Sci. Technol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1161\/CIRCRESAHA.118.313591","article-title":"Immunity and inflammation in atherosclerosis","volume":"124","author":"Wolf","year":"2019","journal-title":"Circ. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"155342","DOI":"10.1016\/j.phymed.2024.155342","article-title":"Poliumoside protects against type 2 diabetes-related osteoporosis by suppressing ferroptosis via activation of the Nrf2\/GPX4 pathway","volume":"125","author":"Xu","year":"2024","journal-title":"Phytomedicine"},{"key":"B48","doi-asserted-by":"publisher","first-page":"4613","DOI":"10.3390\/molecules25204613","article-title":"Nanoformulations to enhance the bioavailability and physiological functions of polyphenols","volume":"25","author":"Yang","year":"2020","journal-title":"Molecules"},{"key":"B49","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1499157","DOI":"10.3389\/fcvm.2025.1499157","article-title":"Identification and validation of key genes associated with cell senescence in acute myocardial infarction","volume":"12","author":"Zhao","year":"2025","journal-title":"Front. Cardiovasc Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1805938\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:08:21Z","timestamp":1779430101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1805938\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":50,"alternative-id":["10.3389\/fphar.2026.1805938"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1805938","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"article-number":"1805938"}}