PCSK9 as an Emerging Target for Cerebrovascular Dysfunction and Neuroinflammation in Ischemic Stroke

Cerebrovascular disease is a leading cause of death and long-term disability worldwide, most commonly manifesting as ischemic stroke. The pathogenesis of ischemic stroke is largely driven by atherosclerotic diseases of the cerebral and extracranial vasculature, where lipid accumulation and vascular inflammation play central roles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key mediator in this process. Elevated circulating PCSK9 contributes to stroke risk and severity across multiple stages of disease progression, promoting atherogenesis, plaque instability, and thrombosis. It exacerbates acute ischemic injury by elevating circulating low-density lipoprotein cholesterol (LDL-C) and promoting vascular inflammation via upregulation of monocyte adhesion, foam cell formation, and cytokine release. Following cerebral ischemia, upregulated PCSK9 also contributes to neuroinflammation within the brain parenchyma, thereby driving secondary neuronal injury and poor neurological outcomes. Preclinical stroke models have shown that PCSK9 inhibition (PCSK9i) is effective within this neurovascular context, attenuating both vascular and neuroinflammatory signaling and thereby limiting ischemic injury. Recent clinical trials have focused on the potential of PCSK9i for broader cardiometabolic indications and stroke prevention, drawing on evidence that treatment can reduce the risk of these events and improve neurological outcomes for patients.