Targeting Ferroptosis for Cerebral Neuroprotection in Ischemic Stroke: Pathophysiological Insights

Chong Song,1, Songlin Tang,2, Yongpan Huang,1, Guangdi Xie,3 Jiayu Tang4 1School of Medicine, Changsha Social Work College, Changsha, Hunan, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Shaoyang College, Shaoyang, Hunan, People’s Republic of China; 3Department of Neurology, Huitong People’s Hospital, Huitong, Hunan, People’s Republic of China; 4Department of Neurology, Brain Hospital of Hunan Province, Changsha, Hunan, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Jiayu Tang, Department of Neurology, Brain Hospital of Hunan Province, Changsha, Hunan, People’s Republic of China, Email tangjiayu1978@163.com Yongpan Huang, School of Medicine, Changsha Social Work College, Changsha, Hunan, People’s Republic of China, Email yongpanhuangyxy@163.comAbstract: Acute ischemic stroke, a leading cause of neurological disability, stemed from cerebral hypoperfusion-induced ischemia/reperfusion (I/R) injury. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death, has emerged as a key pathological driver. Unlike apoptosis, ferroptosis involves glutathione peroxidase 4 (GPX4) inactivation, iron dysregulation, and lethal lipid peroxides. Its preclinical inhibition reduced neuronal loss, demonstrating therapeutic promise. Ischemic injury activated accidental/regulated cell death pathways, with ferroptosis, apoptosis, and pyroptosis dynamically regulated by ischemia duration/severity. Convergent mechanisms included hypoxia-induced mitochondrial dysfunction, iron/lipid peroxidation disrupting blood-brain barrier integrity, glutamate-ferroptosis oxidative crosstalk, and Ca2+ overload via reversed Na+/Ca2+ exchange and NMDA hyperactivity. Clinically, cerebrospinal ferritin elevation and parenchymal iron deposition predicted poor outcomes, prioritizing iron homeostasis modulation. GPX4 activation, ACSL4/LOX inhibition, and ACSL3-mediated MUFA integration have showed efficacy in preclinical models. Translational barriers included poor blood-brain barrier permeability of inhibitors, unvalidated human pathways, and lack of relevant comorbid models. Advancing therapies required biomarker discovery, human tissue validation, and integrated models to bridge mechanisms and clinical translation. Ferroptosis inhibition emerged as a neuroprotective strategy with transformative therapeutic potential for acute ischemic stroke, offering a novel avenue to mitigate neuronal injury and improve clinical outcomes.Keywords: ferroptosis, acute ischemic stroke, ischemia/reperfusion injury, lipid peroxidation, neuroprotection