Gene Number: 3077

Location: 6p22.2

Key Functions: Regulation of systemic iron absorption, modulation of hepcidin signaling, maintenance of iron homeostasis, prevention of iron overload and oxidative damage

HFE (homeostatic iron regulator) encodes a transmembrane glycoprotein structurally similar to major histocompatibility complex (MHC) class I molecules. It associates with β2-microglobulin (β2M) to form a functional complex on the cell surface, primarily in hepatocytes, macrophages, and enterocytes. The HFE protein modulates the interaction between transferrin receptor 1 (TfR1) and transferrin (Tf)—the principal iron-transport protein in plasma—thereby serving as a critical sensor of circulating iron levels.

When plasma transferrin saturation is high, HFE dissociates from TfR1 and interacts with transferrin receptor 2 (TfR2) in hepatocytes. This interaction activates the BMP6–SMAD signaling cascade, leading to upregulation of hepcidin (encoded by HAMP), the master regulator of iron metabolism. Hepcidin binds to ferroportin, the only known cellular iron exporter, inducing its internalization and degradation. This process limits both dietary iron absorption in the duodenum and iron release from macrophages, maintaining iron balance. Conversely, when HFE function is compromised, hepcidin synthesis is downregulated, ferroportin remains active, and unregulated iron influx into the bloodstream occurs.

From a genetic standpoint, loss-of-function mutations in HFE disrupt this regulatory axis. The C282Y (c.845G>A) mutation, the most clinically significant, substitutes cysteine for tyrosine at position 282, impairing disulfide bond formation essential for β2M binding and proper trafficking to the cell membrane. The H63D (c.187C>G) variant, though less deleterious, modifies the α1 domain, subtly altering the HFE–TfR1 interaction. Individuals homozygous for C282Y or compound heterozygous for C282Y/H63D typically exhibit hereditary hemochromatosis (HH)—an autosomal recessive disorder marked by progressive tissue iron overload.

Excessive iron deposition, particularly in the liver, pancreas, heart, and joints, leads to oxidative stress via Fenton chemistry, generating reactive oxygen species (ROS) that damage lipids, proteins, and DNA. This contributes to hepatic cirrhosis, cardiomyopathy, diabetes mellitus, arthropathy, and increased hepatocellular carcinoma (HCC) risk. Notably, the clinical penetrance of HFE mutations varies considerably: although up to 1 in 200 individuals of Northern European descent are C282Y homozygotes, only a subset develop severe iron overload, suggesting a role for modifying loci (e.g., HAMP, BMP2, TMPRSS6) and environmental cofactors such as alcohol intake, infections, or metabolic syndrome.

Molecular and genetic research has expanded the understanding of HFE beyond its classical role in hemochromatosis. HFE expression influences macrophage iron recycling, immune modulation, and cellular proliferation. Iron excess in HFE-deficient states can alter immune cell function, particularly macrophage polarization and T-cell activation, potentially explaining links between iron dysregulation and susceptibility to infections or autoimmune phenomena. Moreover, recent studies have implicated HFE-mediated signaling in mitochondrial function and oxidative phosphorylation, reinforcing its role in redox balance and cellular energy metabolism.

Epigenetic and transcriptomic data suggest that HFE expression is dynamically regulated by inflammatory cytokines such as IL-6 and TNF-α, integrating iron metabolism with the innate immune response. During infection or inflammation, IL-6–induced hepcidin synthesis sequesters iron within cells, limiting its availability to pathogens—a defense mechanism known as nutritional immunity. Dysregulation of this pathway in HFE mutation carriers may therefore contribute to altered infection dynamics and chronic inflammatory conditions.

In summary, HFE functions as a central molecular integrator of systemic iron balance, immune signaling, and oxidative homeostasis. Mutations in this gene represent one of the most well-characterized examples of monogenic metabolic disease, providing deep insights into the interaction between genetics, nutrient sensing, and chronic disease risk. The study of HFE has elucidated not only the pathophysiology of hemochromatosis but also broader principles of metabolic regulation, offering translational implications for liver disease, cardiometabolic disorders, and precision nutrition approaches.