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Cerebral ischemia/reperfusion (I/R) injury-induced neuronal apoptosis contributes to the death and disability in patients with ischemic stroke. However, underlying mechanisms remain elusive and it lacks effective treatment. Here we reported that the expression of casein kinase 2 (CK2) was significantly reduced in brains of middle cerebral artery occlusion/reperfusion (MACO/R) model rats and oxygen-glucose deprivation/reperfusion (OGD/R) model neurons, which was associated with the activation of eIF2-ATF4-CHOP signaling pathway, leading to neuronal apoptosis. Moreover, we found that apelin-13 significantly upregulated CK2 expression and inhibited eIF2-ATF4-CHOP activation, attenuating cerebral I/R injury-induced infarct and neuronal apoptosis in MACO/R model rats and OGD/R model neurons. Furthermore, we demonstrated that the rescue effect of apelin-13 on I/R injury-induced neuronal apoptosis was mediated by Gαi/Gαq-CK2-dependent inhibition of eIF2-ATF4-CHOP activation. These data indicated cerebral I/R injury reduced CK2 expression and activated eIF2-ATF4-CHOP signaling contributing to neuronal apoptosis, and apelin-13 can activate Gαi/Gαq-CK2 signaling attenuating eIF2-ATF4-CHOP-mediated neuronal apoptosis. It provides a novel insight that not only apelin-13 but also CK2 agonists may have therapeutic potential for protecting neurons from I/R injury-induced apoptosis, facilitating post-stroke recovery.CK2 was significantly reduced by I/R injury, which was associated with the activation of eIF2-ATF4-CHOP signaling pathway.Apelin-13 upregulated CK2 and inhibited eIF2-ATF4-CHOP activation, attenuating I/R injury-induced neuronal apoptosis.The rescue effect of apelin-13 on apoptosis was mediated by Gαi/Gαq-CK2-dependent inhibition of eIF2-ATF4-CHOP activation.