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Oxymatrine (OMT) has demonstrated potential in ameliorating cellular senescence. This study aims to investigate the pharmacological properties and underlying mechanisms of OMT in alleviating AS progression. High\u2010fat diet\u2010fed ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice and oxLDL\u2010induced macrophage senescence models were used to study OMT's effects in\u00a0vivo and in\u00a0vitro. Furthermore, OMT's mechanisms were investigated using network pharmacology, pharmacological intervention, gene silencing, molecular docking, Cellular Thermal Shift Assay (CETSA), and Drug Affinity Responsive Target Stability (DARTS) assays. The results demonstrated that OMT inhibited macrophage senescence, thereby improving AS progression. Network pharmacology analysis and biological experiments suggested that the mechanism of OMT improving AS is involving the regulation of SIRT1. Functional validation assays revealed that the effects of OMT were aborted by EX527 and SIRT1 shRNA. OMT enhanced the interaction between SIRT1 and P53, promoting P53 deacetylation and subsequent ubiquitination. Furthermore, Idasanutlin attenuated the functional effects of OMT, which indicated the pivotal role of P53. Molecular docking, CETSA, and DARTS assays confirmed that OMT directly binds to SIRT1 and stabilizes its protein. Our results highlight the potential anti\u2010atherosclerotic effects of OMT both in\u00a0vitro and in\u00a0vivo. Mechanistically, OMT stabilizes SIRT1, enhancing its activity to promote P53 deacetylation, ubiquitination, and degradation. Consequently, this process delays macrophage senescence\u2010induced foam cell formation, ultimately ameliorating AS. Our findings suggest OMT as a promising therapeutic candidate for AS.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70209","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T14:47:31Z","timestamp":1768920451000},"page":"1173-1194","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Oxymatrine Alleviates Atherosclerosis by Regulating Macrophage Senescence via the\n                    <scp>SIRT1<\/scp>\n                    \u2010\n                    <scp>P53<\/scp>\n                    Signaling Pathway"],"prefix":"10.1002","volume":"40","author":[{"given":"Jun","family":"Xiang","sequence":"first","affiliation":[{"name":"The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province Guizhou Medical University  Guiyang Guizhou China"},{"name":"The State Key Laboratory of Functions and Applications of Medicinal Plants, no. 6 Ankang Avenue, 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