Iron Homeostasis and Chronic Liver Disease

Iron is indispensable for oxygen transport, cellular respiration and DNA synthesis, yet its redox activity renders excess iron toxic. The liver acts as both a storage depot and a regulatory hub for systemic iron balance, secreting the peptide hormone hepcidin to control intestinal absorption and macrophage export through the membrane protein ferroportin. In chronic liver disease—whether driven by alcohol, metabolic dysfunction, viral infection or genetic haemochromatosis—disturbances in hepcidin expression and ferroportin function lead to hepatic iron overload. Excess iron catalyses the formation of reactive oxygen species and lipid peroxides, promoting hepatocyte injury, non-apoptotic cell death (ferroptosis) and activation of hepatic stellate cells. The ensuing fibrogenic response replaces functional parenchyma with scar tissue, progressing to cirrhosis and elevated risk of hepatocellular carcinoma. A deeper understanding of iron-driven molecular pathways is critical for refining non-invasive biomarkers, developing iron-modulating therapies and mitigating the global burden of chronic liver disorders.

Research from Nature Portfolio

A foundational study revealed that hepcidin directly suppresses activation of hepatic stellate cells by reducing ferroportin-mediated iron export. Reduced intracellular iron promoted Akt phosphorylation and inhibited TGFβ1-induced Smad3 signalling, attenuating fibrogenesis in toxin- and bile duct-injury models. This work established hepcidin as an antifibrotic agent and demonstrated that cellular iron trafficking is a viable therapeutic target to limit extracellular matrix deposition in chronic liver injury.

Iron Homeostasis and Chronic Liver Disease publication trend

The graph below shows the total number of articles in iron homeostasis and chronic liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Hepcidin: A liver-derived peptide hormone that binds ferroportin, inducing its internalisation and degradation to reduce iron export from enterocytes and macrophages.

Ferroportin: The sole known cellular iron exporter, present on basolateral membranes of enterocytes, macrophages and hepatocytes, regulated post-translationally by hepcidin.

Hepatic stellate cell: A perisinusoidal liver cell that, upon activation by injury or oxidative stress, transdifferentiates into a myofibroblast-like cell, secreting collagen and driving fibrosis.

Ferroptosis: A regulated, iron-dependent form of cell death characterised by accumulation of lipid hydroperoxides, distinct from apoptosis and necrosis.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen, including hydroxyl radicals formed via iron-catalysed Fenton chemistry, which can damage lipids, proteins and DNA.

References

1. Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation. PLOS Pathogens (2023).
2. Hepcidin inhibits Smad3 phosphorylation in hepatic stellate cells by impeding ferroportin-mediated regulation of Akt. Nature Communications (2016).
3. Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis—A Novel Form of Non-Apoptotic Cell Death?. International Journal of Molecular Sciences (2020).
4. Iron at the Interface of Hepatocellular Carcinoma. International Journal of Molecular Sciences (2021).
5. Liver Iron, HFE Gene Mutations, and Hepatocellular Carcinoma Occurrence in Patients With Cirrhosis. Gastroenterology (2007).