The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke

Ferroptosis is a unique form of cell death that was first described in 2012 and plays a significant role in various diseases, including neurodegenerative conditions. It depends on a dysregulation of cellular iron metabolism, which increases free, redox‐active, iron that can trigger Fenton reactions, generating hydroxyl radicals that damage cells through oxidative stress and lipid peroxidation. Lipid peroxides, resulting mainly from unsaturated fatty acids, damage cells by disrupting membrane integrity and propagating cell death signals. Moreover, lipid peroxide degradation products can further affect cellular components such as DNA, proteins, and amines. In ischemic stroke, where blood flow to the brain is restricted, there is increased iron absorption, oxidative stress, and compromised blood–brain barrier integrity. Imbalances in iron‐transport and ‐storage proteins increase lipid oxidation and contribute to neuronal damage, thus pointing to the possibility of brain cells, especially neurons, dying from ferroptosis. Here, we review the evidence showing a role of ferroptosis in ischemic stroke, both in recent studies directly assessing this type of cell death, as well as in previous studies showing evidence that can now be revisited with our new knowledge on ferroptosis mechanisms. We also review the efforts made to target ferroptosis in ischemic stroke as a possible treatment to mitigate cellular damage and death. Cell death by ferroptosis results from disrupted iron metabolism, leading to redox‐active Fenton reactions that generate lipid peroxidation. In ischemic stroke, where blood flow to the brain is limited, elevated iron absorption exacerbates oxidative stress, potentially inducing ferroptotic neuronal death. Studies demonstrate the involvement of ferroptosis in ischemic stroke, prompting exploration of ferroptosis‐targeting therapies.