Exercise-induced myokine irisin protects against obesity-associated ischemic stroke via integrin αVβ5 signalin

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 αVβ5. Conversely, genetic deletion of FNDC5 exacerbated ischemic outcomes, disrupted blood–brain barrier integrity, aggravated neuroinflammation, and reduced integrin αVβ5 expression, collectively mirroring the pathological features reversed by exogenous irisin. Pharmacological blockade of integrin αVβ5 with cilengitide abolished the neuroprotective effects of irisin, establishing the receptor-dependent nature of its actions. These findings demonstrate that the FNDC5/irisin/integrin αVβ5 axis functions as a receptor-dependent, exercise-inducible neuroprotective pathway in obesity-associated ischemic stroke, and identify recombinant irisin as a promising therapeutic candidate for this high-risk population.