Melatonin Ameliorates Cognitive Impairment Following Exertional Heat Stroke by Inhibiting Ferroptosis and Neuroinflammation

<b><i>Aims:</i></b> This study aims to investigate whether melatonin (MLT) exerts protective effects against cognitive impairment following exertional heat stroke (EHS) by modulating ferroportin (Fpn) to alleviate hippocampal ferroptosis and neuroinflammation. <b><i>Results:</i></b> Following EHS, genes such as <i>Mt1</i>, <i>Mt2</i>, and <i>Trf</i> were notably upregulated in the hippocampal tissue, whereas genes such as <i>Slc40a1</i> (encoding Fpn 1) and <i>Il33</i> were downregulated. Kyoto Encyclopedia of Genes and Genomes analysis implicated ferroptosis as a dominant. MLT significantly ameliorated learning and memory deficits observed in EHS mice. This treatment also modulated ferroptosis markers, such as Fpn, xCT, ferritin H, and glutathione peroxidase 4, reduced hippocampal iron overload, and decreased the secretion of proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α (TNF-α). Furthermore, MLT treatment reduced oxidative stress and lipid peroxidation and mitigated mitochondrial and neuronal damage in the hippocampal tissue. Strikingly, conditional Fpn knockout abolished MLT's benefits: Fpn-cKO + MLT mice showed persistent iron accumulation, elevated IL-6 and TNF-α, and failed cognitive recovery. <b><i>Innovation:</i></b> Our study reveals that MLT prevents EHS-induced neurodegeneration by enhancing Fpn-dependent iron efflux, a mechanism that concurrently resolves hippocampal iron overload, suppresses ferroptosis, and dampens neuroinflammation. <b><i>Conclusion:</i></b> Our findings indicate that MLT mitigates EHS-related cognitive impairment by restoring hippocampal iron homeostasis and suppressing neuroinflammation, primarily through Fpn-dependent mechanisms. <i>Antioxid. Redox Signal.</i> 43, 509-527.