The Nrf2-GPX4 axis mitigates ferroptosis-driven early brain injury in experimental subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is a catastrophic cerebrovascular event often resulting from the rupture of intracranial aneurysms, leading to significant brain damage and lasting neurological deficits. Despite advancements in treatment, the mechanisms underlying early brain injury (EBI) following SAH, particularly the role of ferroptosis, remain poorly understood. This study aims to elucidate the impact of Nrf2- glutathione peroxidase 4 (GPX4) pathway on ferroptosis in EBI after experimental SAH. Male Sprague-Dawley rats were subjected to prechiasmatic cistern SAH, with interventions involving Nrf2 modulation using ML385 (a specific inhibitor) or resveratrol (an activator). The results demonstrate that SAH significantly increases iron content, lipid reactive oxygen species (ROS), and malondialdehyde levels while reducing glutathione levels and suppressing GPX4 expression, which promotes ferroptosis. Resveratrol significantly decreases iron content, lipid ROS, and MDA levels; increases GPX4 expression; and restores mitochondrial morphology, whereas the Nrf2 inhibitor ML385 causes opposite changes in these metrics. These findings highlight the crucial role of the Nrf2-GPX4 pathway in regulating ferroptosis following SAH, which suggests it as a potential therapeutic target for mitigating EBI.