{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T15:05:54Z","timestamp":1790521554287,"version":"4.1.0"},"reference-count":41,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,4,29]]},"abstract":"<jats:p>Developed over 70 years ago as an anti-folate chemotherapy agent, methotrexate (MTX) is a WHO \u2018essential medicine\u2019 that is now widely employed as a first-line treatment in auto-immune, inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and Crone's disease. When used for these diseases patients typically take a once weekly low-dose of MTX \u2014 a therapy which provides effective inflammatory control to tens of millions of people worldwide. While undoubtedly effective, our understanding of the anti-inflammatory mechanism-of-action of low-dose MTX is incomplete. In particular, the long-held dogma that this disease-modifying anti-rheumatic drug (DMARD) acts via the folate pathway does not appear to hold up to scrutiny. Recently, MTX has been identified as an inhibitor of JAK\/STAT pathway activity, a suggestion supported by many independent threads of evidence. Intriguingly, the JAK\/STAT pathway is central to both the inflammatory and immune systems and is a pathway already targeted by other RA treatments. We suggest that the DMARD activity of MTX is likely to be largely mediated by its inhibition of JAK\/STAT pathway signalling while many of its side effects are likely associated with the folate pathway. This insight into the mechanism-of-action of MTX opens the possibility for repurposing this low cost, safe and effective drug for the treatment of other JAK\/STAT pathway-associated diseases.<\/jats:p>","DOI":"10.1042\/bst20190803","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T11:35:16Z","timestamp":1585827316000},"page":"559-567","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["How does methotrexate work?"],"prefix":"10.1042","volume":"48","author":[{"given":"Adel M.","family":"Alqarni","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2942-1135","authenticated-orcid":false,"given":"Martin P.","family":"Zeidler","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"2021111915593760300_BST-2019-0803CC1","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1056\/NEJM194806032382301","article-title":"Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid","volume":"238","year":"1948","journal-title":"N. 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