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Whilst research has sought to identify novel atheroprotective therapies targeting inflammation and immunity, several marketed drugs for rheumatological conditions may serve a similar purpose. One such drug, methotrexate, has been used since 1948 for treating cancer and, more recently, for a wide range of dysimmune conditions. Over the last 30\u2009years, epidemiological and experimental studies have shown that methotrexate is independently associated with a reduced risk of cardiovascular disease, particularly in rheumatological patients, and exerts several beneficial effects on vascular homeostasis and blood pressure control. This review article discusses the current challenges with managing cardiovascular risk and the new frontiers offered by drug discovery and drug repurposing targeting inflammation and immunity with a focus on methotrexate. Specifically, the article critically appraises the results of observational, cross-sectional and intervention studies investigating the effects of methotrexate on overall cardiovascular risk and individual risk factors. It also discusses the putative molecular mechanisms underpinning the atheroprotective effects of methotrexate and the practical advantages of using methotrexate in cardiovascular prevention, and highlights future research directions in this area. <\/jats:p>","DOI":"10.1177\/17539447231215213","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T08:09:41Z","timestamp":1703059781000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":26,"title":["Methotrexate and cardiovascular prevention: an appraisal of the current evidence"],"prefix":"10.1177","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8699-1412","authenticated-orcid":false,"given":"Arduino A.","family":"Mangoni","sequence":"first","affiliation":[{"name":"Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"},{"name":"Department of 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