FGL1 & ERFE in Iron Regulation/Homeostasis

In mammalian systems, iron is essential for many biological processes, especially hemoglobin synthesis and oxygen transport. Erythropoiesis is finely coordinated with iron metabolism. Accordingly, anemia is the main consequence of iron deficiency. Iron availability is regulated by hepcidin, a liver-derived hormone that controls iron absorption and iron recycling by blocking the activity of the only known cellular iron exporter ferroportin. When hepcidin is high, ferroportin is degraded, reducing intestinal iron absorption and iron release from stores. When hepcidin is suppressed, more iron enters the circulation.

Figure 1

Iron signaling pathways under hypoxia. Adapted from L. Silvestri; Blood 143, 1208 (2024).

Iron Demand During Erythropoiesis

Red blood cell production is the body’s largest iron-consuming process. During blood loss, anemia recovery, or ineffective erythropoiesis, iron demand rises sharply. To meet this need, hepcidin must be rapidly suppressed so that iron can be mobilized for hemoglobin synthesis and erythrocyte maturation. This response is mainly regulated by erythroferrone (ERFE), fibrinogen-like protein 1 (FGL1), and TMPRSS6 (see Figure 1).

ERFE: The Early Erythroid Signal

ERFE is produced by erythroblasts in response to erythropoietin (EPO) and acts as an early signal of erythropoietic stress. It suppresses hepcidin by binding BMPs, especially BMP6, and inhibiting BMP-SMAD signaling. ERFE rises quickly after blood loss and provides the initial drop in hepcidin needed to release iron. However, ERFE alone does not fully explain long-term hepcidin suppression (see Figure 2 on the kinetics of ERFE and FGL1). For more information on AdipoGen Life Sciences ERFE ELISA Kits. 

FGL1: A Newly Identified Hepcidin Suppressor

FGL1 is a hepatocyte-derived protein induced by hypoxia. Like ERFE, it suppresses hepcidin by antagonizing BMP6 and inhibiting BMP-SMAD signaling. Unlike ERFE, FGL1 rises later (see Figure 2) and remains elevated longer, making it important for sustained iron mobilization during prolonged erythropoietic stress. Its discovery shows that the liver actively contributes to iron regulation beyond hepcidin production. For more information on FGL1& LAG-3 Reagents.

Figure 2

Kinetics of the key actors of Iron regulation Hepcidin, ERFE and FGL1. Adapted from L. Silvestri; Blood 143, 1208 (2024).

TMPRSS6: A Key Negative Regulator of Hepcidin

TMPRSS6 (matriptase-2) is a liver-expressed protease that also suppresses hepcidin. It reduces BMP-SMAD signaling by cleaving hemojuvelin, a co-receptor required for hepcidin induction. By lowering BMP signaling, TMPRSS6 helps maintain iron availability, especially during iron deficiency. Loss of TMPRSS6 function causes inappropriate hepcidin elevation and is linked to iron-refractory iron deficiency anemia (IRIDA).

A Coordinated Regulatory Network

Together, ERFE, FGL1, and TMPRSS6 form a coordinated system that suppresses hepcidin during stress erythropoiesis. Hypoxia via the hypoxia-inducible factor (HIF) stimulates EPO production in the kidney, which drives ERFE release from erythroid cells. At the same time, hypoxic signaling via HIF induces FGL1 and TMPRSS6 in the liver, which further dampens BMP-SMAD signaling. All three pathways converge to increase ferroportin activity and iron availability. This balance supports efficient iron recycling and red blood cell production. When disrupted, it can contribute to anemia of inflammation, IRIDA, β-thalassemia, and iron overload disorders. As key regulators of iron homeostasis and erythropoiesis, Hepcidin, ERFE, FGL1, and TMPRSS6 are important biomarkers and therapeutic targets. Understanding their interactions provides valuable insight into iron-related diseases and new treatment strategies.

Explore our portfolio of antibodies, recombinant proteins, ELISA kits, and research tools for studies in iron regulation, erythropoiesis, hypoxia signaling, and metabolic disease.

LIT: Ironing erythroid cells takes FLG1 and ERFE to tango: L. Silvestri; Blood 143, 1208 (2024) • The hepatokine FGL1 regulates hepcidin and iron metabolism during anemia in mice by antagonizing BMP signaling: U. Sardo, et al.; Blood 143, 1282 (2024) • Fibrinogen-like 1: A hepatokine linking liver physiology to hematology: J. Personnaz, et al.; HemaSphere 8, e115 (2024) • Evaluation of FGL1 as a hepatokine marker in iron deficiency: M. Saboor, et al.; Front. Nutr. 13, 1767385 (2026) 

Biomarkers Assays for Iron Homeostasis Research 

Biologically Active Proteins for Iron Homeostasis Research

VALIDATED Antibodies for Iron Homeostasis Research