From Iron to Depression: The Crosstalk Between the Periphery and Brain

Iron is a crucial micronutrient required for human development and physiological function, with emerging research continuously unveiling novel functions of iron and iron-sulfur (Fe-S) clusters. Recent evidence has further elucidated the homeostatic crosstalk between central and peripheral iron metabolism. Brain iron dyshomeostasis is a classical hallmark of neurodegenerative diseases (NDs). Systemic and central iron disturbances spanning both iron overload and deficiency have also been implicated in the pathogenesis of depression. This review summarizes newly identified physiological functions of iron and the crosstalk between central and peripheral iron metabolism. It further provides recent updates on the mechanisms underlying depression, with a particular emphasis on interactions between the brain and peripheral factors, including gut microbiota (GM), peripheral inflammation, hypothalamus-pituitary-adrenal (HPA) axis, and iron. Finally, the crosstalk between iron and other pathogenic factors in depression is discussed. This review provides a better understanding of iron and its role in depressive disorders and underscores the critical brain-periphery axis, offering novel mechanistic insights and potential therapeutic targets for psychiatric conditions.