Sesamol Mitigates Chronic Iron Overload‐Induced Cognitive Impairment and Systemic Inflammation via IL‐6 and DMT1 Regulation

Scope Excessive iron contributes to oxidative damage and cognitive decline in Alzheimer's disease. Sesamol, a compound in sesame oil that exhibits both anti‐inflammatory and neuroprotective properties, is examined in this study for its ability to alleviate cognitive impairments in iron overload mice model. Methods and results An iron overload model is established by intraperitoneally injecting dextran iron (250 mg kg −1 body weight) twice a week for 6 weeks, while sesamol (100 mg kg −1 body weight) is administered daily for the same length of time. The results demonstrate that sesamol protects spatial working memory and learning ability in iron overload mice, and inhibits neuronal loss and brain atrophy induced by iron overload. Moreover, sesamol significantly decreases interleukin‐6 and malondialdehyde, and increases glutathione peroxidase 4 in the brains of iron overload mice. Additionally, sesamol maintains iron homeostasis in the brain by regulating the expressions of transferrin receptors, divalent metal transporter 1, and hepcidin, and reducing iron accumulation. Furthermore, sesamol suppresses disturbed systemic iron homeostasis and inflammation, particularly liver interleukin‐6 expression. Conclusion These findings suggest that sesamol may be effective in mitigating neuroinflammatory responses and cognitive impairments induced by iron overload, potentially through its involvement in mediating the liver‐brain axis.