Ergosterol Ameliorates Hypoxic-Ischemic Encephalopathy in Mice via Akt/GSK-3β Pathway Activation

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal mortality and long-term neurological disability, with limited therapeutic options. Ergosterol (ERG), a natural sterol with antioxidant, anti-inflammatory, and anti-apoptotic properties that crosses the blood-brain barrier, exhibits neuroprotective potential. Here, we demonstrate that ERG exerts comprehensive neuroprotection in HIE by activating the Akt/GSK-3β pathway. In vitro, ERG significantly improved cell viability, reduced apoptosis, suppressed reactive oxygen species (ROS) accumulation, and inhibited pro-inflammatory cytokine expression in oxygen-glucose deprivation/reoxygenation (OGD/R)-injured HT22 neurons. In vivo, ERG treatment reduced cerebral infarction volume, alleviated histopathological damage and neuronal apoptosis, upregulated neurotrophic proteins (BDNF, PSD95, synaptophysin), and cognitive function in mouse HIE models. Mechanistically, ERG activated Akt phosphorylation and subsequent GSK-3β inhibition, while the Akt inhibitor MK-2206 completely abolished ERG-mediated protection. These findings establish ERG as a promising multi-target therapeutic candidate for HIE through Akt/GSK-3β pathway modulation.