The Red Blood Cell-Liver Axis: A New Framework for Iron Homeostasis and Liver Biology

The liver is traditionally viewed as an organ of metabolism, bile formation, detoxification, and iron storage. Evidence shows that hepatic red blood cell (RBC) handling extends beyond macrophages to include uptake by hepatocytes and liver sinusoidal endothelial cells, forming a multicellular clearance network. This article introduces the RBC-liver axis, through which the liver senses, processes, and responds to RBC-derived material. Daily RBC turnover generates the dominant flux of heme and iron, recycling 25 mg of iron per day, while hepatocytes couple heme-responsive NRF2 signaling to MRP2-mediated bilirubin excretion. Hepcidin emerges as an integrated output of RBC-derived heme and iron flux, inflammation, oxygen tension, redox status, and erythropoietic demand. Evidence supports a biphasic response in which moderate RBC-derived heme and iron flux stimulates hepcidin, whereas excessive hemolysis may dysregulate this response through ERFE-dependent and ERFE-independent mechanisms. Mechanistically, this model integrates BMP6-SMAD signaling with HO-1, KEAP1-NRF2, BACH1, and redox-sensitive H₂O₂-STAT3 signaling amplified by hypoxia. Alcohol-associated liver disease illustrates its clinical relevance by linking enhanced erythrocyte turnover to iron accumulation and mortality. Thus, the liver emerges as a central processor of RBC biology, whose metabolic, protein-producing, lipid-handling, detoxifying, and biliary functions may reflect an evolutionarily conserved blood-processing program.