Iron Metabolism in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic disorders characterised by excessive lipid accumulation in hepatocytes, ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. A growing body of evidence implicates dysregulation of iron homeostasis in both the initiation and progression of NAFLD. Under physiological conditions, systemic iron balance is maintained by the hepcidin–ferroportin axis, which governs cellular iron export and prevents free-iron overload. In NAFLD, alterations in hepcidin expression and ferroportin function can lead to excess labile iron in hepatocytes, generating reactive oxygen species that catalyse lipid peroxidation, mitochondrial injury and endoplasmic reticulum stress. Concurrently, aberrant sequestration of iron in non-parenchymal cells such as hepatic stellate cells promotes fibrogenic activation and extracellular matrix deposition. Circulating iron biomarkers, including ferritin and transferrin saturation, often correlate with disease severity and may serve as prognostic indicators. Therapeutic strategies aimed at restoring iron equilibrium—through modulation of hepcidin, chelation, or targeted inhibition of iron-driven cell death pathways—offer promise in mitigating inflammatory and fibrotic sequelae of NAFLD.

Research from Nature Portfolio

Deficiency of the serine protease matriptase-2 (TMPRSS6), a key negative regulator of hepcidin, has been shown to confer resistance to diet-induced obesity and hepatic steatosis. In models lacking TMPRSS6, elevated hepcidin levels limit iron efflux via ferroportin, reducing parenchymal iron accumulation and protecting against lipid overload. Restoration of iron levels by antagonising hemojuvelin reverses this phenotype, demonstrating that controlled up-regulation of hepcidin can ameliorate fatty liver changes and improve glucose tolerance. These findings underscore the therapeutic potential of tuning the hepcidin axis to prevent or treat NAFLD.

Iron Metabolism in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in iron metabolism in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Hepcidin: A peptide hormone produced by the liver that regulates systemic iron balance by promoting degradation of the iron exporter ferroportin.

Ferroportin: The sole known cellular iron exporter, located on hepatocytes, enterocytes and macrophages, whose activity is inhibited by hepcidin binding.

Ferritin: An intracellular protein complex that stores and sequesters iron in a non-toxic form, serving as a buffer against iron overload.

Ferroptosis: A regulated, iron-dependent form of cell death driven by lipid peroxidation and reactive oxygen species accumulation.

Hepatic stellate cells: Liver-resident pericytes that, upon activation by inflammatory or oxidative signals, differentiate into myofibroblasts and drive fibrogenesis.

References

1. Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH. Cell Metabolism (2024).
2. Do iron homeostasis biomarkers mediate the associations of liability to type 2 diabetes and glycemic traits in liver steatosis and cirrhosis: a two-step Mendelian randomization study. BMC Medicine (2024).
3. Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metabolism (2022).
4. Matriptase-2 deficiency protects from obesity by modulating iron homeostasis. Nature Communications (2018).