Inhibition of Ferroptosis Attenuates Neuron Damage and Improves Cognitive Impairment in Mice Surviving Severe Hypothermia

Survivors of severe hypothermia frequently exhibit cognitive impairments. However, the underlying mechanisms remain inadequately understood. In order to reveal the scientific problem of cognitive dysfunction caused by severe hypothermia, providing an experimental basis for clinical treatment, this study utilized animal models and combined cognitive behavioral, morphological, and molecular biological experiments. The results showed that severe hypothermia leads to an accumulation of iron ions in the cerebral cortex tissue exceeding 70%, while increased Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression enhances sensitivity to ferroptosis. This process results in a nearly 50% decrease in glutathione (GSH) expression and over 50% degradation of glutathione peroxidase 4 (GPX4), leading to GPX4 deactivation and increased lipid peroxidation, which in turn nearly doubles the levels of oxidative products such as MDA and 4NHE. Notably, ferroptosis inhibition using Ferrostatin-1 (Fer-1) effectively mitigates the degenerative death of cerebral cortical neurons induced by severe hypothermia, significantly improving the associated cognitive deficits. These findings suggest that severe hypothermia may induce ferroptosis in cortical neurons through the Nrf2/SLC7A11/GSH/GPX4 signaling axis. Targeted inhibition of ferroptosis has the potential to be a promising therapeutic direction for the prevention and treatment of cognitive impairment caused by severe hypothermia.