Erfe, or erythroferrone, is the main erythroid regulator of hepcidin, a key hormone controlling plasma iron levels and total body iron [1,2,4]. It functions in the iron homeostasis pathway. When erythropoietin from the kidney stimulates new red blood cell production, it also boosts Erfe synthesis in bone marrow erythroblasts. Erfe then suppresses hepcidin synthesis, mobilizing cellular iron stores for heme and hemoglobin synthesis [1,4]. Genetic models are valuable for studying its function.

In ineffective erythropoiesis, an expanded population of erythroblasts pathologically overproduces Erfe, suppressing hepcidin and causing iron overload even in non-transfused patients. This indicates Erfe may be a biomarker for ineffective erythropoiesis and a potential target for treating its systemic effects [1]. In congenital dyserythropoietic anemias (CDAs), another form of ineffective erythropoiesis, Erfe's role in mediating hepatic iron overload has been studied [2]. In cancer cachexia skeletal muscle atrophy, Erfe is upregulated in cachectic cancer patients' muscle biopsies and murine cachexia models, where its expression is driven by STAT3. Knocking down Erfe reduces muscle wasting in cachectic mice, suggesting its involvement in this muscle-wasting condition [3].

In conclusion, Erfe is crucial for iron homeostasis by regulating hepcidin. Its overproduction in ineffective erythropoiesis-related conditions like CDAs and its role in cancer cachexia muscle atrophy highlight its significance in these disease areas. Studies using models like gene knockdown in mice have provided insights into its function, contributing to our understanding of these biological processes and potential therapeutic targets.