Iron deficiency drives metabolic adaptation of red pulp macrophages via FPN-SYK signaling and BCAA catabolism to enhance erythrophagocytosis

Iron deficiency is the most common nutritional disorder worldwide, yet the mechanisms by which individual cell types adjust to iron scarcity remain unclear. Splenic red pulp macrophages (RPMs) are the key cell type for maintenance of systemic iron homeostasis. They manage exceptionally high iron flux by recycling aged red blood cells (RBCs) through erythrophagocytosis, a specialized form of efferocytosis. Yet, how RPMs adapt to iron deficiency is unknown. Surprisingly, we show that RPMs from mildly anemic, iron-deficient (ID) mice exhibit enhanced erythrophagocytic capacity. Proteomic profiling and flow cytometry revealed expansion and activation of lysosomal and mitochondrial networks, accompanied by elevated mitochondrial respiration. This metabolic rewiring and the increase in erythrophagocytosis depended on efficient branched-chain amino acid (BCAA) catabolism. These responses occurred independently of classical M2 polarization and were absent in other macrophage populations. Mechanistically, the low hepcidin-high ferroportin (FPN) axis and SYK kinase activity emerged as key drivers of this functional rewiring. Pharmacological inhibition of SYK or BCAA catabolism reversed the ID phenotype in RPMs. Together, these findings highlight a unique metabolic reprogramming of RPMs that enhances their specialized efferocytic functions during systemic iron scarcity.