We aimed to investigate the role of the brain's major water channel Aquaporin-4 (AQP4) in regulating neuronal pyroptosis, a highly inflammatory form of cell death, following cerebral ischemia.<h4>Methods</h4>Utilizing integrated <i>in vivo</i> and <i>in vitro</i> approaches, we employed AQP4 knockout mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and neuron-astrocyte co-cultures under oxygen-glucose deprivation/reoxygenation (OGD/R) with AQP4 knockdown to investigate the association between AQP4 and neuronal pyroptosis. This evidence concerns the gene AQP4 and brain ischemia.