Hematopoietic Cell Kinase Promotes Cerebral Ischemic Injury and Mitochondrial Dysfunction via p38 Activation in Ischemic Stroke.

Ischemic stroke is a leading cause of death and permanent disability worldwide. There is an urgent need to identify novel therapeutic targets. Through bioinformatics analysis of Gene Expression Omnibus (GEO) datasets and the construction of protein-protein interaction (PPI) network, we identified hematopoietic cell kinase (HCK) as a key regulatory factor in ischemic stroke. In the rat middle cerebral artery occlusion (MCAO) model, we observed that HCK expression was significantly upregulated following cerebral ischemia. HCK knockdown markedly attenuated cerebral injury and mitochondrial dysfunction in MCAO rats. Meanwhile, we observed that HCK expression was significantly upregulated in N2a cells following oxygen and glucose deprivation (OGD) treatment. Silencing of HCK significantly suppressed apoptosis and mitigated mitochondrial dysfunction as evidenced by preventing the decrease in mitochondrial membrane potential (MMP), inhibiting mitochondrial permeability transition pore (mPTP) opening, reducing mitochondrial reactive oxygen species (ROS) production, and inhibiting the aberrant expression of dynamic related protein 1 (DRP1) and mitofusin 2 (MFN2) following OGD treatment. Mechanistically, we demonstrated that HCK acted as an upstream regulator of p38 and mediated OGD-induced N2a cells injury and mitochondrial dysfunction via the activation of p38. Collectively, our findings indicate that HCK plays a significant role in cerebral ischemic injury and mitochondrial dysfunction, highlighting it as a promising therapeutic target for neuroprotective strategies.