{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:22:39Z","timestamp":1792264959303,"version":"4.4.0"},"reference-count":197,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The fibronectin domain-containing protein 5 (FNDC5), or irisin, is an adipo-myokine hormone produced during exercise, which shows therapeutic potential for conditions like metabolic disorders, osteoporosis, sarcopenia, obesity, type 2 diabetes, and neurodegenerative diseases, including Alzheimer\u2019s disease (AD). This review explores its potential across various pathophysiological processes that are often considered independent. Elevated in healthy states but reduced in diseases, irisin improves muscle\u2013adipose communication, insulin sensitivity, and metabolic balance by enhancing mitochondrial function and reducing oxidative stress. It promotes osteogenesis and mitigates bone loss in osteoporosis and sarcopenia. Irisin exhibits anti-inflammatory effects by inhibiting NF-\u03baB signaling and countering insulin resistance. In the brain, it reduces amyloid-\u03b2 toxicity, inflammation, and oxidative stress, enhancing brain-derived neurotrophic factor (BDNF) signaling, which improves cognition and synaptic health in AD models. It also regulates dopamine pathways, potentially alleviating neuropsychiatric symptoms like depression and apathy. By linking physical activity to systemic health, irisin emphasizes its role in the muscle\u2013bone\u2013brain axis. Its multifaceted benefits highlight its potential as a therapeutic target for AD and related disorders, with applications in prevention, in treatment, and as a complement to exercise strategies.<\/jats:p>","DOI":"10.3390\/ijms252413480","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T09:17:58Z","timestamp":1734340678000},"page":"13480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Irisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6408-6478","authenticated-orcid":false,"given":"Ilaria","family":"Paoletti","sequence":"first","affiliation":[{"name":"IRCSS Santa Lucia Foundation, European Center for Brain Research, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7059-7015","authenticated-orcid":false,"given":"Roberto","family":"Coccurello","sequence":"additional","affiliation":[{"name":"IRCSS Santa Lucia Foundation, European Center for Brain Research, 00143 Rome, Italy"},{"name":"Institute for Complex Systems (ISC), National Research Council (C.N.R.), 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nature10777","article-title":"A PGC1-\u03b1-Dependent Myokine That Drives Brown-Fat-like Development of White Fat and Thermogenesis","volume":"481","author":"Wu","year":"2012","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E769","DOI":"10.1210\/jc.2012-2749","article-title":"Irisin Is Expressed and Produced by Human Muscle and Adipose Tissue in Association with Obesity and Insulin Resistance","volume":"98","author":"Ortega","year":"2013","journal-title":"J. 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