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Fibroblast growth factor 21 (FGF21) is involved in various metabolic disorders and neurodegenerative diseases. FGF21 and its co\u2010receptor \u03b2\u2010Kloth are essential in the remyelination process of MS. Metformin, an insulin\u2010sensitizing drug that is the first\u2010line treatment for type 2 diabetes mellitus (T2DM), may have a potential neuroprotective impact by up\u2010regulating the production of FGF21, which may prevent the onset of neurodegenerative diseases including MS. The purpose of this review is to clarify how metformin affects MS neuropathology mechanistically via modifying FGF21. Metformin increases the expression of FGF21. Metformin also increases the expression of \u03b2\u2010Klotho, modulates oxidative stress, reduces glutamate\u2010induced excitotoxicity, and regulates platelet function and coagulation cascades. In conclusion, metformin can enhance the functional activity of FGF21 in counteracting the development and progression of MS. Preclinical and clinical studies are warranted in this regard.<\/jats:p>","DOI":"10.1111\/ejn.70067","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T07:10:40Z","timestamp":1743750640000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Possible Role of Metformin and Fibroblast Growth Factor\u201021 in Multiple Sclerosis Neuropathology: Birds of a Feather Flock Together"],"prefix":"10.1111","volume":"61","author":[{"given":"Ahmad\u00a0A.","family":"Abulaban","sequence":"first","affiliation":[{"name":"College of Medicine King Saud bin Abdulaziz University for Health Sciences  Riyadh Saudi Arabia"},{"name":"Division of Neurology, King Abdulaziz Medical City Ministry of the National Guard Health Affairs  Riyadh Saudi Arabia"},{"name":"King Abdullah International Medical Research Center  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3097-2962","authenticated-orcid":false,"given":"Hayder\u00a0M.","family":"Al\u2010kuraishy","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Medicine, College of Medicine Al\u2010Mustansiriya University  Bagdad Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-8897","authenticated-orcid":false,"given":"Ali\u00a0I.","family":"Al\u2010Gareeb","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Medicine, College of Medicine Al\u2010Mustansiriya University  Bagdad Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0973-2630","authenticated-orcid":false,"given":"Eman\u00a0A.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Veterinary Medicine Suez Canal University  Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mubarak","family":"Alruwaili","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine Jouf University  Sakaka Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2206-7236","authenticated-orcid":false,"given":"Athanasios","family":"Alexiou","sequence":"additional","affiliation":[{"name":"University Centre for Research &amp; Development Chandigarh University  Mohali Punjab India"},{"name":"Department of Research and Development Funogen  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marios","family":"Papadakis","sequence":"additional","affiliation":[{"name":"Department of Surgery II University Hospital Witten\u2010Herdecke, University of Witten\u2010Herdecke  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7817-425X","authenticated-orcid":false,"given":"Gaber","family":"El\u2010Saber\u00a0Batiha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine Damanhour University  Damanhour Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12585"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/13524585211039111"},{"issue":"2","key":"e_1_2_15_4_1","first-page":"43","article-title":"Erectile Dysfunction and Type 2 Diabetes Mellitus: A New Twist","volume":"10","author":"Abdul\u2010Hadi M. 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