The Iron Chaperone PCBP2 Controls Systemic Iron Homeostasis by Regulating Iron Flux in Red Pulp Macrophages

Systemic iron homeostasis critically depends on macrophages for the recycling of iron from senescent erythrocytes. The iron chaperone poly(rC)-binding protein 2 (PCBP2) is considered to direct intracellular iron trafficking. However, its specific role in macrophage-mediated iron redistribution remains unclear. We show that iron deficiency induces PCBP2 expression in macrophages of mice and humans. Mice lacking PCBP2 in macrophages develop features of iron-restricted erythropoiesis, including reduced bone marrow iron, altered peripheral erythrocytes, and suppressed hepcidin levels. Despite medullary iron deficiency, these mice accumulate iron in the spleen. By profiling splenic cell subsets, we identify red pulp macrophages (RPMs) with dysregulated iron homeostasis: although increasing intracellular iron, PCBP2 depletion limits iron bioavailability. We further provide evidence that this paradox reflects defective iron trafficking due to the lack of PCBP2. First, PCBP2 deficiency restricts the metabolically accessible iron pool and promotes ferritin iron sequestration. Second, heme, the primary iron source for RPMs, requires PCBP2 for its degradation and subsequent iron release. Systemically, PCBP2-dependent macrophage iron flux enables adaptation to dietary iron changes by limiting erythropoiesis during iron deficiency and protecting iron-recycling macrophages from iron overload and oxidative stress during iron excess. These findings identify PCBP2-dependent iron trafficking as a regulator linking macrophage iron bioavailability to systemic iron and erythropoietic adaptation.