Targeting Ferroptosis Pathways for Synaptic Protection in Sevoflurane‐Induced Cognitive Impairment: A Nanomedicine Approach

BACKGROUND: Postoperative cognitive dysfunction (POCD) is an increasingly recognized neurological complication following surgery, particularly in elderly patients. It significantly hinders recovery and impairs the quality of life. Sevoflurane, a commonly used volatile anesthetic, has been implicated in enhancing the incidence and severity of POCD. At the molecular level, synaptic dysfunction is a major contributor to cognitive decline associated with POCD. Recent studies have highlighted ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, as a critical mechanism behind synaptic damage and cognitive decline. METHODS: This review synthesizes current research on the role of ferroptosis in POCD, focusing on its impact on synaptic dysfunction. We also explore the potential of nanomedicine, particularly intelligent responsive nanodrug delivery systems, in targeting ferroptotic pathways. These nanoplatforms, with their high brain delivery efficiency and specificity, have been shown to modulate ferroptosis signaling and reduce neuronal injury, thereby potentially promoting cognitive recovery. RESULTS: Ferroptosis plays a significant role in exacerbating cognitive deficits by disrupting synaptic membranes and mitochondria, which contribute to synaptic dysfunction. Emerging evidence suggests that interventions targeting ferroptosis pathways can mitigate these effects, offering a novel therapeutic avenue for POCD. Nanomedicine approaches, especially those utilizing responsive nanodrug delivery systems, have shown promise in effectively targeting ferroptotic pathways with high specificity, leading to reductions in synaptic injury and enhanced cognitive recovery. CONCLUSION: Ferroptosis is a key mechanism driving synaptic dysfunction and cognitive decline in POCD. Targeting ferroptotic pathways using nanomedicine-based strategies holds considerable promise for mitigating POCD and promoting cognitive recovery. Further research is needed to optimize these therapeutic approaches for clinical application in POCD management.