Iron homeostasis at the interface of nutrition, infection, and iron supplementation

Iron is an essential micronutrient that plays a central role in oxygen transport, mitochondrial respiration, DNA synthesis, immune regulation, and numerous enzymatic reactions. Because both iron deficiency and iron overload adversely affect health, systemic and cellular iron homeostasis is tightly regulated through coordinated mechanisms involving intestinal absorption, macrophage-mediated recycling, iron storage, and the hepcidin-ferroportin axis. During infection and inflammation, the host restricts iron availability through nutritional immunity, thereby limiting pathogen proliferation while influencing immune cell function and iron distribution. This review provides an integrated overview of iron homeostasis by linking nutritional factors, inflammatory regulation, infection dynamics, and iron supplementation strategies. The molecular mechanisms governing intestinal iron absorption are summarized together with dietary factors influencing iron bioavailability, including vitamin C, phytates, polyphenols, calcium, dietary fiber, and dietary patterns. The central role of the hepcidin-ferroportin axis in inflammation-induced hypoferremia and its clinical implications for celiac disease, inflammatory bowel disease, aging, and pregnancy are also discussed. Particular emphasis is placed on the dual role of iron in host defense, highlighting how nutritional immunity restricts extracellular pathogens while exerting distinct effects on intracellular microorganisms and adaptive immune responses. The benefits and limitations of iron supplementation are critically evaluated, emphasizing gastrointestinal tolerance, oxidative stress, gut microbiota alterations, dysbiosis, and infection risk. Overall, iron metabolism should be regarded as a dynamic network linking nutrition, immune regulation, microbial ecology, and clinical therapeutics. A comprehensive understanding of these interactions may facilitate personalized iron replacement strategies that effectively correct iron deficiency while preserving intestinal homeostasis and antimicrobial defense.