Ferroptosis and futile recanalization after mechanical thrombectomy in acute ischemic stroke: mechanisms, risk factors, predictive models and therapeutic interventions

Acute ischemic stroke (AIS) remains a leading cause of mortality and long-term disability worldwide. Endovascular mechanical thrombectomy (EVT) has revolutionized stroke treatment by enabling rapid recanalization of occluded cerebral vessels. However, a significant proportion of patients experience futile recanalization, where successful vessel reopening fails to translate into favorable functional outcomes. Emerging evidence highlights ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, as a critical mechanism contributing to neuronal damage in ischemic stroke, particularly during reperfusion injury. This comprehensive review examines the intricate relationship between ferroptosis and futile recanalization following mechanical thrombectomy. We systematically explore the molecular mechanisms underlying ferroptosis in the context of cerebral ischemia-reperfusion injury, including iron metabolism dysregulation, lipid peroxidation cascades, glutathione depletion, and mitochondrial dysfunction. Multiple factors contribute to futile recanalization, including patient demographics (age, comorbidities), stroke characteristics (severity, infarct volume, collateral status), procedural variables (time to treatment, recanalization quality), and post-procedural complications (hemorrhagic transformation, reperfusion injury). We review current predictive models, including nomograms and machine learning algorithms, that integrate clinical, radiological, and biomarker data to stratify patient risk. Importantly, we discuss potential therapeutic interventions targeting ferroptosis pathways, such as iron chelators, lipophilic antioxidants, and ferroptosis-specific inhibitors. The integration of ferroptosis biomarkers into predictive models may enhance risk stratification and guide personalized treatment strategies. Future research should focus on validating ferroptosis-targeted therapies in clinical trials, developing real-time monitoring techniques, and establishing standardized protocols for neuroprotective interventions during mechanical thrombectomy. A deeper understanding of ferroptosis mechanisms and their contribution to futile recanalization may pave the way for novel therapeutic approaches to improve stroke outcomes.