# Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): The Multifaceted Biology, Diseases, and Pharmaceutical Interventions

## TL;DR

PCSK9 inhibitors lower cholesterol and may help prevent and treat ischemic stroke by multiple mechanisms, offering new hope for stroke therapy.

## Contribution

This review systematically consolidates the mechanisms and clinical potential of PCSK9 inhibitors in stroke prevention and treatment.

## Key findings

- PCSK9 inhibitors reduce LDL cholesterol by blocking PCSK9's degradation of LDL receptors.
- They offer neuroprotective and vasculoprotective effects through LDLR-independent pathways.
- PCSK9 inhibitors may improve endothelial function and modulate immune and metabolic responses.

## Abstract

Ischemic stroke remains a leading cause of global disability and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent lipid‐lowering agents with expanding therapeutic potential. Beyond robust low‐density lipoprotein cholesterol reduction, accumulating evidence suggests these drugs may confer benefits in ischemic stroke prevention and management. However, challenges regarding accessibility, real‐world efficacy, and integration into combination therapies persist, necessitating a comprehensive evidence synthesis. This review systematically consolidates the molecular mechanisms of PCSK9 inhibition and classifies current inhibitors. We delineate recent preclinical advances underscoring their neuroprotective and vasculoprotective effects, alongside critical findings from major clinical trials. These developments highlight promising avenues for both secondary prevention and acute‐phase treatment strategies. Collectively, this synthesis establishes a foundational framework for positioning PCSK9 inhibitors as transformative agents in stroke therapeutics and paves the way for precision neurovascular medicine.

Summary of PCSK9 inhibitor mechanisms. PCSK9 inhibitors (PCSK9‐i) primarily lower LDL‐cholesterol (LDL‐C) by blocking PCSK9‐mediated degradation of hepatic LDL receptors (LDLR), enhancing LDL clearance. Beyond LDLR‐dependent effects, PCSK9‐i exert multiple benefits via LDLR‐independent pathways. These include anti‐inflammatory effects, antioxidant actions, and improved endothelial function. Additionally, PCSK9‐i may modulate immune responses, thrombosis, and metabolic pathways. They also influence plaque stability by decreasing smooth muscle cell proliferation and oxidative stress.