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Age is the most significant nonmodifiable risk factor for stroke, and with an aging population, there is an urgent need for effective prevention and treatment strategies. Physical inactivity is a strong risk factor for stroke, and exercise has long been held as a promising approach to improve poststroke outcomes. During exercise, the myokine irisin is released as a product of a type 1 membrane protein cleavage that is encoded by the fibronectin type III domain containing 5 (FNDC5) gene. This review summarizes recent literature on irisin\u2019s role in ischemic stroke, examining central effects, stroke risk, poststroke functional outcomes, and exogenous administration. Irisin has value as a prognostic marker for risk stratification. Low levels of irisin correlate with worse outcomes and higher mortality in patients with ischemic stroke. Irisin may also be a key to the benefits of exercise, particularly for high-intensity resistance training, which significantly increases irisin levels. Beyond exercise, exogenous irisin is neuroprotective in murine models, reducing brain edema, inflammation, and apoptosis, and increasing blood-brain barrier integrity and brain-derived neurotrophic factor levels. This underscores irisin\u2019s potential to mitigate ischemic damage and promote recovery. Human trials are necessary to validate these findings and explore the feasibility of irisin-based interventions in acute stroke care. This review lays a foundation for future research to clarify irisin\u2019s therapeutic benefits, establish optimal exercise protocols, and explore exogenous irisin as a novel intervention for ischemic stroke.<\/jats:p>","DOI":"10.1152\/jn.00027.2025","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T07:20:17Z","timestamp":1742973617000},"page":"1320-1328","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Examining a role for irisin in treating cerebral ischemia"],"prefix":"10.1152","volume":"133","author":[{"given":"Jack","family":"Bayfield","sequence":"first","affiliation":[{"name":"University of British Columbia","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna R.","family":"Elford","sequence":"additional","affiliation":[{"name":"University of British 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