ZnT3 knockout also prevented mitochondrial translocation of p-STAT3, attenuated mitochondrial dysfunctions, and abolished zinc overload-induced BBB permeability following I/R.<h4>Conclusion</h4>This study suggests that zinc accumulation in microvessels contributes to I/R-induced BBB damage through JAK2/STAT3 signaling and highlights a potential therapeutic target for preserving vascular integrity after stroke. Here, JAK2 is linked to Stroke.