FAM96A functions as a novel pace controller for iron uptake to maintain iron homeostasis and erythropoiesis.

Iron is indispensable for various biological processes, among which erythropoiesis is a privileged iron consumer to synthesize hemoglobin. FAM96A, also known as cytosolic iron-sulfur protein assembly 2 A (CIA2A), is a conserved protein involved in cytosolic iron-sulfur cluster assembly but also harboring a canonical signal peptide for secretion. Here, we unveil a previously unrecognized role of autocrine FAM96A in maintaining iron homeostasis and erythroid differentiation. Fam96a-/- mice exhibit anemia with impaired recovery, featuring arrested erythroblast differentiation and blocked CD71+Ter119- to CD71+Ter119+ transition. Notably, Fam96a-/- bone marrow and spleen cells exhibit iron overload, elevated oxidative stress, and ferroptosis, all of which are rescued by FAM96A protein application. Mechanistically, secreted FAM96A binds TFRC extracellular domain, reducing TFRC-transferrin binding affinity to limit excessive iron uptake. Our findings identify FAM96A as a novel regulator of TFRC-dependent iron homeostasis, providing insights into erythropoietic disorders and therapeutic strategies.