Targeting Ferroptosis for Cerebral Neuroprotection in Ischemic Stroke: Pathophysiological Insights.
Source: PubMed, NCBI / U.S. National Library of Medicine
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 Caoverload via reversed Na/Caexchange 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 s
Abstract
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 Caoverload via reversed Na/Caexchange 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.