Iron And Heme Metabolism
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Iron And Heme Metabolism

My research on iron metabolism ranges from cellular iron sensing to genetic iron disorders, non-invasive measurement of hepatic iron and the emerging RBC–liver axis.

Early work established iron regulatory protein 1 as a redox-sensitive regulator and showed how extracellular hydrogen peroxide alters cellular iron uptake. Subsequent studies examined hepcidin regulation by sustained low-level peroxide, hypoxia and hepatocyte–endothelial cell crosstalk.

Clinical projects included the first German family with hereditary hyperferritinemia-cataract syndrome and the development of room-temperature susceptometry for non-invasive quantification of hepatic iron.

Recent work extended this research from classical iron regulation to the role of red blood cells in hepatic iron loading. We were the first to demonstrate that hepatocytes can directly ingest entire oxidized red blood cells by efferocytosis. Together with erythrophagocytosis by macrophages and phosphatidylserine-dependent clearance by liver sinusoidal endothelial cells, these findings establish the liver as a central site of whole-red-cell clearance and provide a direct mechanism linking alcohol-mediated hemolysis to hepatic iron overload and progressive liver injury.

RBC–Liver Axis, Hemolysis and Erythrophagocytosis

More recent work has established the red blood cell–liver axis as a major extension of our research on iron and heme metabolism. Studies in alcohol-related liver disease demonstrated enhanced red blood cell turnover and alcohol-mediated hemolysis, linking erythrocyte damage to anemia, AST elevation, hepatic iron loading and progressive liver injury.

We subsequently identified several complementary pathways of hepatic red blood cell clearance. Hepatocytes were shown to directly ingest oxidized red blood cells by efferocytosis, while macrophages remove damaged erythrocytes by erythrophagocytosis and liver sinusoidal endothelial cells recognize and clear phosphatidylserine-exposing red blood cells. Together, these findings identify the liver as a central organ of whole-red-cell clearance and provide a mechanistic connection between alcohol-mediated hemolysis, iron overload and liver disease progression.

Further information

This comprehensive textbook, co-edited with Markus Heilig, integrates current knowledge on alcohol use, alcohol-related diseases and their biological, clinical and therapeutic dimensions. It also provides further background on iron metabolism, erythrophagocytosis and red blood cell turnover, as well as on the effects of alcohol on the liver, iron homeostasis and bone marrow.

For additional background, technical details and original research data on non-invasive hepatic iron measurement, please visit my dedicated Susceptometry Homepage.

Selected publications

• IRP1 activation by extracellular oxidative stress in the perfused rat liver. Mueller S et al. J Biol Chem. 2001;276(25):23192–23196.
• Hyperferritinaemia-cataract syndrome: worldwide mutations and phenotype of an increasingly diagnosed genetic disorder. Millonig G et al. Hum Genomics. 2010;4(4):250–262.
• Sustained submicromolar H2O2 levels induce hepcidin via signal transducer and activator of transcription 3 (STAT3). Millonig G et al. J Biol Chem. 2012;287(44):37472–37482.
• Sensitive and non-invasive assessment of hepatocellular iron using a novel room-temperature susceptometer. Mueller J et al. J Hepatol. 2017;67(3):535–542.
• Novel insights into alcoholic liver disease: iron overload, iron sensing and hemolysis. Mueller S et al. J Transl Int Med. 2022;10(2):92–124.
• Direct ingestion of oxidized red blood cells (efferocytosis) by hepatocytes. Zheng C et al. Hepat Med. 2024;16:65–77.
• Evidence for alcohol-mediated hemolysis and erythrophagocytosis. Zheng C et al. Redox Biol. 2025;85:103742.
• Phosphatidylserine-dependent clearance of damaged red blood cells by liver sinusoidal endothelial cells in alcohol-related liver disease. Li S et al. Biology (Basel). 2026;15(9):699.