Unveiling melatonin's multifaceted actions against ferroptotic neurotoxicity in ischemic stroke

Ferroptosis, an iron-mediated form of programmed cell death, is increasingly recognized for its role in neurodegenerative diseases, with relevance to ischemic stroke, a condition that creates a permissive environment for this process. The prevalence of ischemic stroke is steadily increasing, with its mortality rates rising startlingly in recent years. The urgency of timely intervention is of utmost importance, as failure to treat patients within the narrow therapeutic window often results in severe neurological damage, including severe paralysis or mortality. The pathology of ischemic stroke has been investigated to identify the underlying mechanism and determine efficient therapeutic strategies. Melatonin, a functionally versatile natural indoleamine, has shown promise in deferring neurodegenerative processes, including those associated with stroke. Melatonin exerts pleiotropic biological roles, including being a potent antioxidant, anti-inflammatory, iron chelator, neuroprotector, promoter of neurogenesis, and immune modulator. Recent studies on melatonin have also identified its efficacy in mitigating key events of ferroptosis, introducing it as an anti-ferroptosis agent. Herein, we highlight the prevailing concept of the pathophysiology of ischemic stroke, with emphasis on the emerging significance of ferroptotic neurotoxicity. Furthermore, we discussed recent research on the application of melatonin as a remedial intervention for ischemic stroke associated with ferroptosis.