Ferroptosis in ischemic stroke: mechanisms, pathological implications, and therapeutic strategies Original paper

What was reviewed?

This review focused on the role of ferroptosis in ischemic stroke and how this distinct form of cell death—driven by iron-dependent lipid peroxidation—contributes to neuronal injury in stroke. The authors outlined the core molecular pathways involved in ferroptosis, including iron dysregulation, glutathione depletion, and the inactivation of GPX4. The paper further highlighted how ferroptosis amplifies stroke damage by interacting with neuroinflammation and mitochondrial dysfunction, providing a deeper understanding of its role in stroke pathology. Finally, the review explored various therapeutic strategies aimed at modulating ferroptosis to reduce ischemic damage, including pharmacological inhibitors and emerging nanomedicine and gene therapy approaches.

Who was reviewed?

The review synthesized findings from multiple experimental models, including rodent ischemic stroke models, in vitro neuronal cultures, and human postmortem tissue. It focused on how ferroptosis contributes to ischemic neuronal death and its intersection with neuroinflammation and oxidative stress in these models. The authors also discussed therapeutic approaches tested in preclinical trials and clinical contexts, considering the complexities and potential for translation into stroke therapy.

What were the most important findings?

The review clarified that ferroptosis is a significant contributor to neuronal death during ischemic stroke, particularly through iron dysregulation and lipid peroxidation. Increased levels of labile iron from hemoglobin degradation and disrupted iron transport catalyze Fenton reactions, producing hydroxyl radicals that initiate lipid peroxidation in neuronal membranes. This process is exacerbated by impaired antioxidant defenses, particularly the GPX4/GPX4-Glutathione axis, which normally detoxifies lipid hydroperoxides. The review also emphasized that mitochondrial dysfunction and endoplasmic reticulum stress further amplify the damage caused by ferroptosis, creating a vicious cycle of injury. Importantly, the paper highlighted therapeutic strategies aimed at inhibiting ferroptosis, such as lipid peroxidation inhibitors (e.g., ferrostatin-1, liproxstatin-1) and iron chelators (e.g., Deferoxamine), which have shown promise in preclinical studies by reducing infarct size and improving functional recovery. However, translating these findings to human stroke therapy faces challenges, particularly regarding narrow therapeutic windows and the potential toxicity of therapies that affect iron or lipid metabolism. The review also identified FABP5 as a potential biomarker for ferroptosis, which could help track stroke severity and monitor therapeutic response.

What are the greatest implications of this study/ review?

Clinically, this review presents ferroptosis as a critical pathogenic amplifier in ischemic stroke and suggests that targeting ferroptosis could improve patient outcomes by limiting neuronal death and reducing neuroinflammation. The key implication for clinicians is that therapeutic strategies should consider the temporal dynamics of ferroptosis, as the activation of ferroptosis in the early stages of stroke injury may exacerbate neuronal damage. Developing targeted therapies that inhibit ferroptosis while minimizing risks to normal iron and lipid metabolism could offer a new treatment avenue for ischemic stroke patients, particularly when combined with neuroprotective and anti-inflammatory strategies. The identification of FABP5 as a biomarker offers a promising tool to monitor ferroptosis-related pathology, which could help personalize stroke treatment regimens and improve therapeutic windows for intervention.