Iron Metabolism and Alcohol-Induced Liver Injury

Iron is indispensable for oxygen transport, energy production and enzymatic reactions, yet its redox activity requires tight regulation. Under normal conditions, dietary iron is absorbed in the duodenum, bound to transferrin in plasma and stored in hepatocytes as ferritin. Hepcidin, a liver‐derived peptide, governs systemic iron balance by inducing internalisation of the iron exporter ferroportin. Chronic alcohol consumption disrupts this equilibrium by suppressing hepcidin synthesis, upregulating intestinal iron absorption and promoting hepatic iron deposition. Excess iron catalyses formation of reactive oxygen species, leading to lipid peroxidation, mitochondrial impairment and activation of non‐apoptotic cell death pathways such as ferroptosis. Accumulated iron also provokes inflammatory signalling and stellate‐cell activation, driving fibrogenesis and progression to cirrhosis. Understanding the interplay between iron homeostasis and alcohol‐mediated hepatotoxicity is crucial for identifying biomarkers of disease severity and novel therapeutic targets.

Research from Nature Portfolio

A seminal study has elucidated how hepatic and macrophage iron overload in severe alcoholic hepatitis induces the metalloprotease ADAM17, enhancing shedding of TNF-α and the macrophage marker sCD163. Elevated labile iron pools trigger oxidative‐stress and upregulate iron loading receptors and CD163 signalling. In vitro and patient data indicate that iron chelation or blockade of ADAM17 attenuates inflammatory gene expression and cytokine release. These findings position iron‐driven ADAM17 activation at the nexus of macrophage‐mediated inflammation, suggesting adjunctive strategies for patients with iron‐overloaded alcoholic hepatitis.

Iron Metabolism and Alcohol-Induced Liver Injury publication trend

The graph below shows the total number of articles in iron metabolism and alcohol-induced liver injury across all publications each year (not limited to Nature Index journals).

Technical terms

Hepcidin: A peptide hormone produced by hepatocytes that regulates iron egress by inducing degradation of the iron exporter ferroportin.

Ferroptosis: An iron‐dependent form of regulated cell death characterised by lipid peroxidation and glutathione peroxidase 4 inactivation.

Glutathione peroxidase 4 (GPx4): A selenoenzyme that detoxifies lipid hydroperoxides, preventing ferroptosis.

Labile iron pool: The bioavailable cellular fraction of iron capable of catalysing reactive oxygen species formation.

Transferrin receptor 1: A cell‐surface protein that mediates uptake of transferrin‐bound iron into cells.

Oxidative stress: A state of imbalance between reactive oxygen species production and antioxidant defences, leading to cellular damage.

References

1. Alcohol Metabolism-mediated Oxidative Stress Down-regulates Hepcidin Transcription and Leads to Increased Duodenal Iron Transporter Expression*. Journal of Biological Chemistry (2006).
2. Ferroptosis contributes to ethanol-induced hepatic cell death via labile iron accumulation and GPx4 inactivation. Cell Death Discovery (2023).
3. Iron-Overload triggers ADAM-17 mediated inflammation in Severe Alcoholic Hepatitis. Scientific Reports (2018).
4. Preventive effects of lactoferrin on acute alcohol-induced liver injury via iron chelation and regulation of iron metabolism. Journal of Dairy Science (2024).
5. Liver Iron Loading in Alcohol-Associated Liver Disease. American Journal Of Pathology (2022).