Ferroptosis Targeting: A Novel Therapeutic Strategy Against Anesthetic-Induced Neurotoxicity

Anesthetic-induced neurotoxicity (AIN), particularly postoperative cognitive dysfunction and related perioperative neurocognitive disorders, remains a significant clinical challenge. Ferroptosis—an iron-dependent, lipid peroxidation-driven regulated cell death—has emerged as a key mechanism in preclinical models of anesthetic neurotoxicity. However, administration contexts (e.g., developmental, aged, spinal, or ototoxic) differ in patient populations, exposure paradigms, and tissue -specific outcomes. Preclinical evidence indicates that anesthetics like propofol, sevoflurane, and isoflurane trigger ferroptosis via iron dysregulation, antioxidant depletion, and lethal lipid peroxidation, contributing to neuronal injury and cognitive decline.Pharmacological inhibition of ferroptosis-associated pathways confers neuroprotection in these experimental models, although these findings remain strictly preclinical and do not establish clinical efficacy. This review first outlines core ferroptosis mechanisms, then details the distinct molecular pathways by which various anesthetics induce ferroptosis, and finally summarizes recent advances in ferroptosis-targeted neuroprotection. Crucially, all current evidence is derived exclusively from preclinical studies; clinical translation remains to be established. Moreover, ferroptosis’s relative contribution versus other cell death pathways likely varies across developmental stages, tissue types, and exposure conditions. Nonetheless, targeting ferroptosis represents a promising therapeutic strategy that warrants further investigation in well-designed translational studies to assess its potential for mitigating AIN across diverse clinical contexts. Targeting ferroptosis in anesthetic neurotoxicity: anesthetics trigger ferroptosis via iron overload, GPX4/GSH depletion, and lipid peroxidation, driving cognitive dysfunction. Pharmacological ferroptosis inhibition (e.g., Fer-1, Liproxstatin-1) blocks this cascade, offering neuroprotection against anesthetic-induced neurotoxicity.