{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:53:49Z","timestamp":1790610829030,"version":"4.1.0"},"reference-count":139,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["BG-RRP-2.004-0007-C01"],"award-info":[{"award-number":["BG-RRP-2.004-0007-C01"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities. Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component. Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut\u2013brain axis. Neuroendocrine findings such as hypothalamic\u2013pituitary\u2013adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities. Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise. Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME\/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance.<\/jats:p>","DOI":"10.3390\/ijms27010268","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:50:42Z","timestamp":1766969442000},"page":"268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome"],"prefix":"10.3390","volume":"27","author":[{"given":"Dobrina","family":"Dudova","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-3299","authenticated-orcid":false,"given":"Martina","family":"Bozhkova","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0522-5682","authenticated-orcid":false,"given":"Steliyan","family":"Petrov","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9028-6937","authenticated-orcid":false,"given":"Ralitsa","family":"Nikolova","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6395-4109","authenticated-orcid":false,"given":"Teodora","family":"Kalfova","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9028-2192","authenticated-orcid":false,"given":"Mariya","family":"Ivanovska","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8657-1548","authenticated-orcid":false,"given":"Katya","family":"Vaseva","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Nikolova","sequence":"additional","affiliation":[{"name":"National Reference Laboratory of Immunology, National Centre of Infectious and Parasitic Diseases, 1504 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2616-894X","authenticated-orcid":false,"given":"Ivan N.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Centre of Infectious and Parasitic Diseases, 1504 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12967-020-02269-0","article-title":"Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome\/myalgic encephalomyelitis (CFS\/ME)","volume":"8","author":"Lim","year":"2020","journal-title":"J. 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