Precision medicine targeting ferroptosis in cerebrovascular diseases

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pathology

Background:

• Ferroptosis, a regulated cell death, significantly contributes to secondary brain injury in cerebrovascular diseases (CVDs).
• Current antiferroptotic therapies face challenges in clinical translation due to the heterogeneity of CVDs.
• A uniform approach to inhibiting ferroptosis overlooks distinct pathophysiological mechanisms across different CVD subtypes.

Purpose of the Study:

• To propose a pathology-guided framework for understanding ferroptosis in diverse CVDs.
• To delineate subtype-specific ferroptotic cascades in ischemic stroke, hemorrhagic stroke, and vascular dementia.
• To advocate for precision medicine by emphasizing mechanism-stratified interventions for CVDs.

Main Methods:

• Review of existing literature on ferroptosis mechanisms in cerebrovascular diseases.
• Deconstruction of ferroptosis pathways, including iron metabolism and oxidative stress defenses, in different CVD models.
• Analysis of lipid peroxidation vulnerabilities and antioxidant capacity in relation to specific CVD pathologies.

Main Results:

• Ischemic stroke involves endogenous iron accumulation and impaired nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant defenses.
• Hemorrhagic stroke is characterized by acute exogenous heme influx, triggering ferroptosis.
• Vascular dementia exhibits a lowered threshold for oligodendrocyte ferroptosis due to chronic hypoperfusion.

Conclusions:

• Cerebrovascular diseases exhibit distinct ferroptosis mechanisms, necessitating subtype-specific therapeutic strategies.
• Precision medicine in CVD requires interventions tailored to specific ferroptotic cascades, rather than a one-size-fits-all approach.
• Understanding the nuances of iron overload and lipid vulnerability is key to developing effective antiferroptotic therapies for CVDs.