Iron as an immunometabolic signal in infection and inflammation

Iron availability is dynamically remodeled during infection and inflammation and has traditionally been interpreted within the framework of nutritional immunity, where iron sequestration restricts microbial growth. Increasing evidence, however, indicates that inflammatory iron redistribution has broader immunological consequences. Systemic and cell-intrinsic iron levels actively shape immune cell production, differentiation, metabolic configuration, and effector function across innate and adaptive immune compartments. Rather than uniformly suppressing immunity, inflammation-driven hypoferremia selectively biases hematopoiesis and immune output, while locally regulated cellular and subcellular iron handling determines microbe-specific immune effector functions. In addition, the availability of metabolically active iron further defines immunometabolic state by regulating mitochondrial respiration, tricarboxylic acid cycle activity, and redox balance, thereby shaping both immune cell function and the host-pathogen interface. Together, these observations support a view of iron as an instructive immunometabolic signal that integrates systemic regulation with cellular and organelle-specific programs during infection and inflammation. This review synthesizes recent evidence across these organizational scales, highlights emerging trade-offs between host defense and iron homeostasis, and discusses how mechanistic insight into iron-sensitive immune pathways may inform strategies to modulate inflammation and antimicrobial immune effector function.