A cell-nonautonomous heme acquisition pathway enables erythroid hemoglobinization under stress

Heme, an iron-containing cofactor, is synthesized in mitochondria by an eight-enzyme pathway. Although cells were thought to manage heme autonomously, over 1,000 proteins contribute to its production, transport, and regulation. During terminal erythroid differentiation, mitochondria are discarded yet hemoglobin production continues, implying a cell-nonautonomous heme supply. We show that, under stress, erythroblasts import heme through the permease Heme Responsive Gene 1 (HRG1), which localizes to the plasma membrane and accumulates during stress erythropoiesis, the emergency program that expands red cell output. HRG1 loss impaired heme uptake, inhibited terminal erythroid differentiation, and caused anemia. In β-thalassemic mice, partial HRG1 loss reduces ineffective erythropoiesis, underscoring the importance of balanced heme import. These findings reveal intercellular heme sharing and identify HRG1 as a potential therapeutic target in hemoglobinopathies.