{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T14:50:01Z","timestamp":1780325401596,"version":"3.54.1"},"reference-count":86,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sibylla-Hesse Foundation (MAESTRO-ME project)"},{"name":"The Open Medicine Foundation Canada (REMEDIAL project)"},{"name":"The National MEFM Action Network (MAPLE-LEAF project)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations. In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0\u201350 pg\/mL), normal (51\u2013200 pg\/mL), and high (&gt;200 pg\/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM. Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune\/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM. These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.<\/jats:p>","DOI":"10.3390\/ijms26167670","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T11:41:53Z","timestamp":1754653313000},"page":"7670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia"],"prefix":"10.3390","volume":"26","author":[{"given":"Ghazaleh","family":"Azimi","sequence":"first","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Office 2.17.027, Azrieli Research Center, CHU Sainte-Justine, 3175 Cote-Ste-Catherine Road, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3577-3551","authenticated-orcid":false,"given":"Wesam","family":"Elremaly","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Office 2.17.027, Azrieli Research Center, CHU Sainte-Justine, 3175 Cote-Ste-Catherine Road, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3301-069X","authenticated-orcid":false,"given":"Mohamed","family":"Elbakry","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Office 2.17.027, Azrieli Research Center, CHU Sainte-Justine, 3175 Cote-Ste-Catherine Road, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, GG, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Franco","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Office 2.17.027, Azrieli Research Center, CHU Sainte-Justine, 3175 Cote-Ste-Catherine Road, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Godbout","sequence":"additional","affiliation":[{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Office 2.17.027, Azrieli Research Center, CHU Sainte-Justine, 3175 Cote-Ste-Catherine Road, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Stomatology, Faculty of Dentistry, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ejpain.2006.06.005","article-title":"Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: A systematic review","volume":"11","author":"Meeus","year":"2007","journal-title":"Eur. 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