Abstract

AAV-mediated GPX4 overexpression attenuates cognitive decline in CCH mice. • GPX4 overexpression blocks ferroptosis and neuroinflammation in CCH mice brain and in OGD-treated microglia. Chronic cerebral hypoperfusion (CCH), a core pathological mechanism of vascular cognitive impairment, induces cognitive deficits closely associated with ferroptosis; however, previous studies have not focused on hippocampus-specific microglial damage. In this study, we systematically investigated the mechanism of Gpx4-regulated ferroptosis on cognitive function, neuroinflammation, and white matter damage by constructing a mouse model of CCH with microglia-specific overexpression of glutathione peroxidase 4 (Gpx4) and by establishing a model of microglial oxygen-glucose deprivation (OGD) in vitro. We found that Gpx4 overexpression in CCH mice significantly attenuated hippocampal ferroptosis, preserved the integrity of white matter fiber bundles, and inhibited the expression of inflammatory factors IL-1β, IL-6, TNF-α, CCL3, and CCL2 (with the most significant decrease in CCL2). In vitro, we demonstrated that intervention of OGD microglia with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Gpx4 overexpression could reduce microglial death, intracellular iron ion aggregation, and lipid peroxidation. The present study reveals that selective modulation of microglial Gpx4 in the hippocampus mitigates CCH-induced cognitive dysfunction through a cause-effect axis: ferroptosis suppression functions as the primary trigger that attenuates neuroinflammation, thereby conferring downstream protection on white matter microstructure. These findings support the pharmacological activation of Gpx4 expression to improve vascular cognitive impairment.