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However, not all members of myokines have been thoroughly studied. Here, we identify myonectin, an exercise\u2010induced myokine, as a new regulator of cerebral ischemia\u2013reperfusion (I\/R) injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO\/R) in wild\u2010type mice and skeletal muscle\u2010specific myonectin\u2010knockout mice. Laser speckle contrast imaging (LSCI) and TTC staining were used to assess cerebral injury. HT22 and BV2 cells were utilized to mimic I\/R\u2013associated cellular damage using oxygen\u2013glucose deprivation and reoxygenation (OGD\/R). Intravenous recombinant myonectin was administered to assess therapeutic effects on I\/R injury. Immunohistochemistry, TUNEL, ELISA, and Western blotting assays were performed to detect morphological and molecular changes in cells and tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Exercise elevated serum and brain myonectin and reduced infarct size and neuronal damage in wild\u2010type but not myonectin\u2013deficient mice after MCAO\/R. Systemic myonectin administration significantly protected against cerebral I\/R injury. Mechanically, myonectin exerted neuroprotective effects by suppressing excessive autophagic apoptosis and microglia\u2010mediated neuroinflammation thorough activation of the PI3K\/Akt\/mTOR pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Skeletal muscle\u2010derived myonectin protects the brain from I\/R injury, contributing to exercise benefits via muscle\u2013brain communication. Myonectin may serve as a promising therapeutic agent against cerebral I\/R injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71137","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:30:27Z","timestamp":1789194627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise\u2010Induced Myonectin Protects Against Cerebral Ischemia\u2013Reperfusion Injury"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7391-4118","authenticated-orcid":false,"given":"Jing","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National, Laboratory for Marine Science and Technology  Qingdao 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