Anesthesia-Induced Ferroptosis: Bidirectional Regulation and Molecular Mechanisms in Cardio-Cerebral Injury

Perioperative use of common anesthetics-including sevoflurane, propofol, and dexmedetomidine-may induce cardio-cerebral injury via ferroptosis, an iron-dependent form of cell death. We introduce the "Molecular Switches", proposing that these drugs act as tissue-specific switches regulating ferroptosis bidirectionally. Their effect (promote or inhibit) depends critically on local factors: receptor expression profiles, metabolic status, baseline redox tone, and post-translational modifications of key proteins like glutathione peroxidase 4 (GPX4). High-risk organs like heart and brain, characterized by elevated metabolic demands, polyunsaturated fatty acid (PUFA)-rich membranes, and stringent iron homeostasis, express unique molecular switch configurations explaining their susceptibility. During ischemia-reperfusion injury (IRI), leveraging this principle allows protective anesthetic strategies: targeting the nuclear factor erythroid 2-related factor 2 (Nrf2)/GPX4/solute carrier family 7 member 11 (SLC7A11) antioxidant axis enhances endogenous defenses, while inhibiting Acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid peroxidation limits damage initiation. Crucially, effective myocardial protection prioritizes mitochondrial function recovery and iron efflux modulation, whereas cerebroprotection centers on preserving neuronal iron homeostasis and blood-brain barrier (BBB) integrity-distinct applications derived directly from understanding tissue-specific molecular switches. Addressing clinical translation challenges (limited drug specificity, complex polypharmacy effects, biomarker gaps), we advocate for developing personalized anesthetic protocols informed by molecular switch profiling, employing nanocarriers for targeted delivery across the BBB, and establishing AI-driven predictive models based on ferroptosis biomarkers. This framework provides novel insights for optimizing perioperative cardio-cerebral protection.