Targets for Iron Overload

Understanding the roles of targets provides insights into the pathogenesis of iron-overload disorders such as hereditary hemochromatosis, iron-loading anemias, and neurodegenerative diseases with iron accumulation. Therapeutic strategies could involve modulating the activity or expression of these proteins to restore normal iron homeostasis, reduce iron-induced oxidative damage, and alleviate the symptoms associated with iron-overload.

Direct Regulators of Iron Metabolism

HAMP, HFE, SLC11A2 (DMT1), SLC40A1, and TMPRSS6 are directly involved in the regulation of iron absorption, utilization, and storage. Mutations or dysregulation of these genes can lead to iron-overload conditions.

Hepcidin Antimicrobial Peptide (HAMP)

Hepcidin is a peptide hormone produced by the liver that controls systemic iron levels by binding to ferroportin, the only known cellular iron exporter, triggering its degradation. Decreased hepcidin levels lead to increased iron absorption and release from stores, causing iron accumulation. Mutations affecting HAMP expression or function are directly linked to iron-overload diseases like hereditary hemochromatosis.

Homeostatic Iron Regulator (HFE)

The HFE protein interacts with the transferrin receptor to regulate iron uptake and hepcidin expression. Mutations in the HFE gene (particularly C282Y and H63D) are the most common cause of hereditary hemochromatosis. These mutations impair hepcidin regulation, leading to excessive intestinal iron absorption and systemic iron-overload.

Solute Carrier Family 11 Member 2 (SLC11A2/DMT1)

DMT1 is the primary iron transporter responsible for the uptake of dietary non-heme iron in the duodenum and for iron transport within cells. Increased expression or activity of DMT1 enhances intestinal iron absorption, potentially leading to iron-overload. Mutations affecting DMT1 function can disrupt iron homeostasis.

Solute Carrier Family 40 Member 1 (SLC40A1/Ferroportin)

Ferroportin is the only known cellular iron exporter, present in enterocytes, macrophages, and hepatocytes. Mutations in SLC40A1 can cause Type 4 Hemochromatosis (Ferroportin Disease). Certain mutations make ferroportin resistant to hepcidin, leading to unregulated iron export into the bloodstream and accumulation in organs, resulting in iron-overload.

Transmembrane Serine Protease 6 (TMPRSS6/Matriptase-2)

TMPRSS6 negatively regulates hepcidin expression by cleaving Hemojuvelin (HJV), a co-receptor necessary for hepcidin induction. Loss-of-function mutations in TMPRSS6 lead to increased hepcidin levels and iron-refractory iron deficiency anemia (IRIDA). Conversely, reduced TMPRSS6 activity can decrease hepcidin levels, increasing iron absorption and potentially contributing to iron-overload. TMPRSS6 is therefore a critical regulator of iron homeostasis.

Transcription Factors and Signaling Proteins

EPAS1 (HIF-2α), HNF4A, STAT6, and JAK3 influence iron homeostasis through regulation of gene expression and signaling pathways that modulate hepcidin levels and iron metabolism.

Endothelial PAS Domain Protein 1 (EPAS1)

EPAS1, also known as Hypoxia-Inducible Factor-2α (HIF-2α), is a transcription factor activated under low oxygen conditions. HIF-2α upregulates genes involved in iron absorption, such as Divalent Metal Transporter 1 (DMT1) and Duodenal Cytochrome B (Dcytb). Overactivation of EPAS1 can lead to increased intestinal iron absorption, contributing to systemic iron-overload. Mutations or conditions that stabilize HIF-2α may exacerbate iron accumulation in the body.

Hepatocyte Nuclear Factor 4 Alpha (HNF4A)

HNF4A is a transcription factor that regulates the expression of numerous hepatic genes, including those involved in metabolism and iron homeostasis. HNF4A influences the expression of hepcidin, the master regulator of iron metabolism. Dysregulation of HNF4A can lead to altered hepcidin levels, affecting iron absorption and potentially contributing to iron-overload disorders.

Signal Transducer and Activator of Transcription 6 (STAT6)

STAT6 is activated by cytokines like IL-4 and IL-13, influencing Th2 immune responses. Immune signaling can alter iron metabolism. For instance, Th2 cytokines may modulate hepcidin expression indirectly. However, the direct involvement of STAT6 in iron-overload requires further investigation.

Janus Kinase 3 (JAK3)

JAK3 is involved in the signal transduction of various cytokines crucial for immune function. While JAK3 itself is not directly involved in iron metabolism, cytokine signaling pathways, especially involving IL-6, can influence hepcidin expression via the JAK/STAT pathway. Abnormal JAK3 activity could indirectly affect iron homeostasis by modulating hepcidin levels during inflammatory responses.

Proteins Involved in Oxidative Stress and Cell Death

GPX4 and RIPK1 are implicated in cellular responses to iron-induced oxidative stress and ferroptosis, linking them indirectly to the consequences of iron-overload.

Glutathione Peroxidase 4 (GPX4)

GPX4 is an essential enzyme that reduces lipid hydroperoxides, protecting cells from oxidative damage. Connection to Iron-overload enhances the production of reactive oxygen species (ROS), leading to lipid peroxidation and cell death through a process called ferroptosis. GPX4 deficiency exacerbates ferroptosis, while its proper function mitigates iron-induced oxidative damage. Thus, GPX4 is crucial in protecting cells during iron-overload conditions.

Receptor-Interacting Serine/Threonine Kinase 1 (RIPK1)

RIPK1 is involved in signaling pathways that regulate apoptosis, necroptosis, and inflammation. Iron-overload can induce oxidative stress and cell death. RIPK1-mediated pathways may be activated in response to cellular damage caused by excess iron, contributing to tissue injury in iron-overload conditions.

Neurodegeneration and Iron Accumulation

APP and SNCA are associated with neurodegenerative diseases where iron accumulation exacerbates pathology, highlighting a connection between iron-overload and neuronal dysfunction.

Amyloid Beta Precursor Protein (APP)

APP is not only implicated in Alzheimer's disease but also plays a role in iron metabolism. APP possesses ferroxidase activity, facilitating the oxidation of Fe²⁺ (ferrous iron) to Fe³⁺ (ferric iron), which is essential for iron export via ferroportin.

Dysregulation or altered expression of APP can disrupt normal iron export from neurons, leading to iron accumulation in the brain. Excessive iron contributes to oxidative stress and may exacerbate neurodegenerative processes, highlighting a potential link between APP and iron-overload conditions in neural tissues.

Synuclein Alpha (SNCA)

Alpha-synuclein is a protein implicated in Parkinson's disease, forming aggregates known as Lewy bodies. Excess iron in the brain can promote alpha-synuclein aggregation, enhancing neurotoxicity. Iron-induced oxidative stress may contribute to the misfolding and oligomerization of SNCA, linking iron-overload to neurodegenerative processes.

Other Targets

The roles of DHODH, QRFPR, and ST14 in iron-overload conditions are less well-defined and may involve indirect or context-dependent mechanisms.

Dihydroorotate Dehydrogenase (Quinone) (DHODH)

DHODH is a mitochondrial enzyme involved in pyrimidine biosynthesis, essential for DNA and RNA production. While DHODH does not directly regulate iron metabolism, mitochondrial function is highly dependent on iron-containing enzymes. Iron-overload can impair mitochondrial function, which may, in turn, affect enzymes like DHODH. Conversely, alterations in DHODH activity could influence redox balance and oxidative stress, potentially impacting iron homeostasis indirectly.

Pyroglutamylated RFamide Peptide Receptor (QRFPR/GPR103)

QRFPR is a G-protein-coupled receptor activated by neuropeptides involved in stress and energy balance. There is currently limited evidence directly linking QRFPR to iron metabolism or iron-overload disorders. Further research is needed to elucidate any potential relationship.

ST14 Transmembrane Serine Protease Matriptase (ST14)

Matriptase activates various substrates involved in cellular growth, development, and homeostasis. There is limited evidence directly associating matriptase with iron metabolism. However, since proteases can influence signaling pathways, it's possible that matriptase indirectly affects iron homeostasis. Further research is needed to clarify this relationship.

Transferrin Receptor (TFRC/TfR1)

TfR1 mediates the uptake of transferrin-bound iron into cells via receptor-mediated endocytosis. Overexpression of TFRC can increase cellular iron uptake, potentially leading to iron accumulation and toxicity. Alterations in TFRC regulation can thus contribute to iron-overload at the cellular level.