Zinc alleviates stroke development through autophagy-mediated modulation of immune microenvironment

Area of Science:

• Neuroscience
• Immunology
• Metabolomics

Background:

• Stroke is a major global cause of death and disability, increasingly understood as a neuroinflammatory, immune-mediated condition.
• Acute ischemia in stroke triggers immune cell activation and infiltration, worsening neuronal damage.
• The role of zinc, an essential micronutrient with immunomodulatory and autophagy-regulating properties, in stroke-related neuroinflammation is not well-defined.

Purpose of the Study:

• To investigate if zinc protects against ischemic brain injury.
• To determine if zinc modulates autophagy and the immune microenvironment in the context of stroke.

Main Methods:

• Genome-wide association studies (GWAS) and NHANES cohort analyses assessed zinc intake and stroke risk.
• Pathway enrichment, PPI network analysis, and diagnostic modeling identified zinc-responsive immuno-autophagic regulators (ZIARs).
• Immune cell infiltration analysis and in vitro ischemia-reperfusion experiments evaluated zinc's effects on autophagy and neuronal survival.

Main Results:

• Higher zinc levels correlated with lower stroke prevalence (GWAS OR ~0.141, NHANES adjusted OR ~0.96).
• Zinc-associated genes were enriched in autophagy and inflammatory pathways (e.g., PI3K-Akt, NF-κB).
• In vitro, zinc pretreatment reduced neuronal death and oxidative stress, an effect dependent on autophagy; zinc attenuated excessive autophagy, promoting survival.

Conclusions:

• Zinc provides neuroprotection in ischemic stroke by normalizing autophagic flux and reducing neuroinflammation via ZIAR regulation.
• These findings highlight the crosstalk between immune and autophagy pathways in zinc's neuroprotective effects.
• Zinc represents a potential therapeutic strategy for stroke prevention and intervention.