Sphk2 in ischemic stroke pathogenesis: Roles, mechanisms, and regulation strategies

Ischemic stroke, a leading cause of mortality and long-term disability worldwide, is characterized by acute cerebral artery occlusion leading to neuronal death and functional deficits. Despite advances in reperfusion therapies, the lack of effective neuroprotective agents underscores the need for novel therapeutic strategies targeting secondary injury mechanisms. Sphingosine kinase 2 (Sphk2) has emerged as a pivotal regulator in ischemic stroke pathogenesis, mitigating blood-brain barrier leakage, neuroinflammation, and neuronal survival through its downstream metabolite, sphingosine-1-phosphate. This review comprehensively examines the roles and mechanisms of Sphk2 in ischemic stroke, highlighting its potential in anti-inflammation and neuroprotection. We discuss current therapeutic approaches targeting Sphk2, including pharmacological activation, natural compounds and gene therapy. Future directions focus on developing Sphk2-specific agonists, optimizing delivery strategies, and exploring cell type-specific adeno-associated virus vectors and engineered exosomes modulation to maximize therapeutic efficacy while minimizing off-target effects. By synthesizing current knowledge and identifying gaps, this review provides a roadmap for harnessing Sphk2 as a therapeutic target to improve stroke outcomes.