The study identifies erythroferrone (ERFE), a new hormone produced by erythroblasts, as a key regulator of iron metabolism during stress erythropoiesis. ERFE suppresses hepcidin, a major iron-regulatory hormone, allowing increased iron absorption and mobilization from stores. In mice, ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage, leading to delayed recovery from blood loss. ERFE expression is significantly increased in *Hbb*^*Th3/+*^ thalassemia intermedia, contributing to systemic iron overload. The study also demonstrates that ERFE acts directly on the liver to suppress hepcidin mRNA expression, independent of the BMP/Smad signaling pathway. In β-thalassemia intermedia mice, ablation of *Fam132b* (the gene encoding ERFE) reduces hepcidin levels and decreases hepatic iron overload. These findings highlight ERFE's role in regulating iron homeostasis and suggest it as a potential therapeutic target for iron-loading anemias.The study identifies erythroferrone (ERFE), a new hormone produced by erythroblasts, as a key regulator of iron metabolism during stress erythropoiesis. ERFE suppresses hepcidin, a major iron-regulatory hormone, allowing increased iron absorption and mobilization from stores. In mice, ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage, leading to delayed recovery from blood loss. ERFE expression is significantly increased in *Hbb*^*Th3/+*^ thalassemia intermedia, contributing to systemic iron overload. The study also demonstrates that ERFE acts directly on the liver to suppress hepcidin mRNA expression, independent of the BMP/Smad signaling pathway. In β-thalassemia intermedia mice, ablation of *Fam132b* (the gene encoding ERFE) reduces hepcidin levels and decreases hepatic iron overload. These findings highlight ERFE's role in regulating iron homeostasis and suggest it as a potential therapeutic target for iron-loading anemias.