Targeting ferroptosis and oxidative stress crosstalk: a new frontier in stroke neuroprotection

Cerebral ischemia-reperfusion (I/R) injury triggers a complex cycle of biochemical disturbances that accelerate neuronal death and functional deterioration. Among the various regulated cell death pathways involved, ferroptosis has recently emerged as a central mechanism linking iron imbalance, lipid peroxidation, and oxidative damage. Excessive generation of reactive oxygen species (ROS) during reperfusion overwhelms endogenous antioxidant defenses, disrupts mitochondrial function, and enhances lipid peroxidation, thereby initiating ferroptotic signaling. Iron overload-driven by increased transferrin receptor expression, ferritinophagy, and Fenton chemistry-further amplifies lipid peroxide accumulation and GPX4 inactivation, establishing a self-propagating cycle of oxidative injury. Several key signaling pathways modulate this interplay between oxidative stress and ferroptosis. Activation of Nrf2 promotes the transcription of antioxidant and iron-regulatory genes, offering substantial protection against ferroptotic damage. In contrast, HIF-1α exerts a dual role; although it supports metabolic adaptation and angiogenesis under hypoxia, its prolonged activation may promote lipid peroxidation and ferroptotic vulnerability. Casein kinase 2 (CK2) also contributes to the redox landscape by regulating the activity of NADPH oxidase, STAT3/SOD2, and HIF-1α, leading to context-dependent protective or detrimental outcomes. This review examines the molecular crosstalk between oxidative stress and ferroptosis in ischemia-reperfusion injury and summarizes key pharmacological and natural agents that target these pathways to achieve neuroprotection. In response to recent translational concerns, the review further emphasizes cell-type-specific ferroptotic vulnerability, GPX4-independent defense systems, blood-brain barrier and pharmacokinetic barriers, clinical readiness, safety limitations, and unresolved controversies that must be addressed before ferroptosis-targeted interventions can be advanced for stroke therapy.