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Pharmacol."],"abstract":"<jats:p>Ischemic stroke in the context of obesity represents a growing clinical challenge, yet obesity-specific neuroprotective strategies remain largely unexplored. Here, we investigated whether exercise-induced irisin, a myokine generated by proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) in skeletal muscle, confers neuroprotection in a high-fat diet (HFD)-induced obese mouse model of transient middle cerebral artery occlusion (MCAO). Treadmill exercise reduced infarct size and restored circulating and cerebral FNDC5\/irisin levels that were suppressed by obesity and ischemic injury. Intraperitoneal administration of recombinant irisin recapitulated these protective effects, reducing infarct volume and neurological deficits while upregulating the tight junction proteins occludin and claudin-5, suppressing microglial activation, promoting M2 macrophage polarization, and inhibiting NLRP3 inflammasome-mediated pyroptosis, as evidenced by reductions in cleaved caspase-1 and gasdermin D protein. Irisin treatment also significantly increased the protein expression of its receptor, integrin \u03b1V\u03b25. Conversely, genetic deletion of FNDC5 exacerbated ischemic outcomes, disrupted blood\u2013brain barrier integrity, aggravated neuroinflammation, and reduced integrin \u03b1V\u03b25 expression, collectively mirroring the pathological features reversed by exogenous irisin. Pharmacological blockade of integrin \u03b1V\u03b25 with cilengitide abolished the neuroprotective effects of irisin, establishing the receptor-dependent nature of its actions. These findings demonstrate that the FNDC5\/irisin\/integrin \u03b1V\u03b25 axis functions as a receptor-dependent, exercise-inducible neuroprotective pathway in obesity-associated ischemic stroke, and identify recombinant irisin as a promising \u201c\u201cexercise mimetic\u201d\u201c with therapeutic potential for this high-risk population.<\/jats:p>","DOI":"10.3389\/fphar.2026.1893339","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:47:49Z","timestamp":1785905269000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise-induced myokine irisin protects against obesity-associated ischemic stroke via integrin \u03b1V\u03b25 signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Eun Bi","family":"Ma","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]},{"name":"Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School","place":["Gwangju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Jun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Global Innovative Drugs, The Graduate School of Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyangju","family":"Kang","sequence":"additional","affiliation":[{"name":"BioApplications Inc.","place":["Pohang, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Ju","family":"Sohn","sequence":"additional","affiliation":[{"name":"BioApplications Inc.","place":["Pohang, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Ho","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School","place":["Gwangju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo Young","family":"Huh","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]},{"name":"Department of Global Innovative Drugs, The Graduate School of Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.2147\/NDT.S67184","article-title":"Cognitive impairment and memory dysfunction after a stroke diagnosis: a post-stroke memory assessment","volume":"10","author":"Al-Qazzaz","year":"2014","journal-title":"Neuropsychiatr. 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