The most abundant transition metal in the human body and arguably the most consequential metal in biology. Iron is essential for oxygen transport, energy metabolism, DNA synthesis, and immune defense -- yet its redox activity makes it dangerous when uncontrolled. The tension between iron's necessity and its toxicity drives pathology across virtually every disease domain covered in this wiki, from neurodegeneration to cancer to infectious disease to postpartum depression.
Chemical Properties and Forms
- Transition metal cycling between Fe2+ (ferrous) and Fe3+ (ferric) states -- this redox cycling is both its biological utility and its danger.
- Fenton reaction: Fe2+ + H2O2 -> Fe3+ + OH- + OH* generates hydroxyl radicals, the most reactive oxygen species [doroszkiewicz 2023 common trace metals alzheimers parkinsons].
- Regulated by the hepcidin-ferroportin axis: hepcidin controls iron absorption from dietary sources, macrophages, and body stores [bao 2024 iron homeostasis intestinal immunity gut microbiota].
- Key transport proteins: DMT1 (SLC11A2) for import, ferroportin (SLC40A1) for export, transferrin for plasma transport, ferritin for storage [bao 2024 iron homeostasis intestinal immunity gut microbiota].
- Iron regulatory proteins (IRP1/2) sense cellular iron and post-transcriptionally regulate transferrin receptor and ferritin expression [bao 2024 iron homeostasis intestinal immunity gut microbiota].
- Nickel can oxidize iron in iron-sulfur clusters and iron-containing hydroxylases, disrupting IRP-1/IRP-2, transferrin receptor, and ferritin levels [salnikov 2008 metal carcinogenesis].
Sources of Exposure
Dietary
- Heme iron (meat, fish) is more bioavailable than non-heme iron (plants, fortified foods).
- Iron-fortified infant cereals and formulas are significant sources for infants.
- Baby food mixed jars highest in Fe (10.5 mg/kg in meat jars) among food categories [gonzalez suarez 2022 baby food jars essential toxic elements].
Supplementation
- Iron supplementation is standard prenatal and postpartum care.
- Iron supplementation effects on gut microbiota: increased Enterobacteriaceae and decreased Lactobacillus in infants; increased Bacteroidetes in African children [bao 2024 iron homeostasis intestinal immunity gut microbiota].
Environmental and Occupational
- Iron is a co-exposure in welding fumes alongside manganese and nickel [racette 2017 manganese parkinsonism welders].
- Tampons contain measurable Fe (detected in 100% of samples) [shearston 2024 tampons metal exposure].
Health Effects
Ferroptosis
Ferroptosis -- iron-dependent programmed cell death via lipid peroxidation -- is an emerging central concept linking iron to disease across multiple organ systems.
- Iron catalyzes Fenton reactions generating hydroxyl radicals that drive lipid peroxidation; GPX4 (glutathione peroxidase 4) downregulation removes the brake on ferroptotic cell death [pendergrass 2026 microbial metallomics parkinsons ferroptosis].
- Ferroptosis serves as the convergent cell death mechanism in both gut epithelial damage and dopaminergic neuron loss in PD [pendergrass 2026 microbial metallomics parkinsons ferroptosis].
- Iron-dependent phospholipid peroxidation in renal tubular cells; iron-restricted diet protective in CKD animal models [mishra 2022 molecular mechanisms heavy metals ckd].
- GPX4 identified as ferroptosis regulator in thyroid cancer [brylinski 2025 trace elements thyroid diseases].
- Ferroptosis is emerging as a therapeutic target in cancer treatment by inducing oxidative stress [bao 2024 iron homeostasis intestinal immunity gut microbiota].
Neurodegeneration
- Parkinson's disease: Iron accumulation in the substantia nigra is a PD hallmark; iron chelation (deferiprone) shows some benefit in trials [doroszkiewicz 2023 common trace metals alzheimers parkinsons].
- Pheomelanin-neuromelanin hypothesis: In redheads (MC1R variants), higher pheomelanin-to-eumelanin ratio in neuromelanin reduces iron sequestration, increasing free iron and ferroptotic vulnerability [pendergrass 2026 pheomelanin neuromelanin parkinsons redheads].
- Alzheimer's disease: Iron accumulation in hippocampus and cortex; transferrin receptor and ferritin alterations in disease states [doroszkiewicz 2023 common trace metals alzheimers parkinsons].
- Dementia with Lewy bodies: Fe and alpha-synuclein interactions create a vicious cycle linking iron dysregulation to protein aggregation [scholefield 2024 brain metallomics dementia].
- Widespread copper decreases and localized iron/selenium changes distinguish DLB, AD, and PDD metallomic profiles [scholefield 2024 brain metallomics dementia].
Postpartum Depression
- Postpartum anemia significantly increases PPD risk: RR = 1.887 (95% CI: 1.255-2.838) across 10 studies; pregnancy anemia RR = 1.240 [azami 2019 anemia ppd meta analysis].
- Low serum ferritin (<1 ug) associated with 3.98-fold increased PPD risk [azami 2019 anemia ppd meta analysis].
- Iron deficiency alters concentrations of cytochrome C, dopamine, serotonin, and GABA, with adverse effects on brain function [tian 2020 iron supplementation ppd protocol].
- Iron is essential for dopamine synthesis; iron supplementation is a proposed PPD treatment [etebary 2010 ppd serum trace elements].
- Elevated copper alongside iron deficiency in PPD suggests a Cu/Fe imbalance in pathophysiology [etebary 2010 ppd serum trace elements].
Thyroid Disease
- Iron deficiency decreases TPO activity, leading to reduced T3/T4 synthesis and increased TSH [brylinski 2025 trace elements thyroid diseases].
- 58% of Hashimoto's thyroiditis patients have iron deficiency anemia [brylinski 2025 trace elements thyroid diseases].
- Fe deficiency impairs TPO activity and is associated with increased autoantibodies (TPOAb, TgAb) [kravchenko 2023 thyroid hormones minerals AITD].
- Iron facilitates tumor cell proliferation in thyroid cancer via hepcidin [brylinski 2025 trace elements thyroid diseases].
- Iron has immunomodulating effects on M1/M2 macrophage polarization [kravchenko 2023 thyroid hormones minerals AITD].
Cardiovascular Disease
- Iron decreased in AMI patients (0.95 vs 1.17 ug/mL); Fe/Cu ratio significantly decreased [lim 2023 plasma metallomics ami].
- Fe/Cu ratio is a more sensitive AMI biomarker than individual element concentrations [lim 2023 plasma metallomics ami].
- Cu/Se and Fe/Cu ratios incorporated into random forest model achieving AUC of 0.942 for AMI classification [lim 2023 plasma metallomics ami].
Cancer
- Iron elevated in prostate cancer (1.96 vs 1.24 ug/ml, p<0.05); increased Fe may promote oxidative stress via Fenton reaction [saleh 2020 serum trace elements prostate cancer].
- Iron overload (elevated ferritin) correlates with insulin resistance and preclinical T2D; hemochromatosis increases hepatocarcinoma risk [khan 2014 metals type2 diabetes].
Diabetes
- Elevated ferritin correlates with insulin resistance at preclinical stages of T2D [khan 2014 metals type2 diabetes].
- Fe oxidizes biomolecules, decreasing insulin secretion [khan 2014 metals type2 diabetes].
Role in Nutritional Immunity and Infectious Disease
Iron is the centerpiece of nutritional immunity -- the host strategy of sequestering metals to starve invading pathogens.
Host Iron Sequestration
- Transferrin and lactoferrin bind extracellular iron; hemopexin and haptoglobin scavenge heme from lysed red blood cells [cassat 2012 metal acquisition staphylococcus aureus].
- Lactoferrin concentrations increase 6.6-fold with bacterial vaginosis and 11.5-fold with Trichomonas vaginalis infection; Lf is positively associated with serum hepcidin and ferritin [roberts 2019 lactoferrin genital infections iron].
- Iron-deficient women had lower vaginal lactoferrin and were more susceptible to genital infections [roberts 2019 lactoferrin genital infections iron].
Pathogen Iron Acquisition
- S. aureus: Produces staphyloferrin A and B siderophores; uses Isd heme acquisition system; hemolysins lyse RBCs to release hemoglobin; heme is the preferred iron source during infection [cassat 2012 metal acquisition staphylococcus aureus].
- S. pneumoniae: Requires iron for viability; uses hemoglobin and heme (NOT transferrin or lactoferrin) as sole iron sources via 22 and 37 kDa membrane proteins [romero espejel 2013 streptococcus pneumoniae iron].
- Siderophores are the most diagnostically important metallophores; detection via mass spectrometry can identify pathogens faster than culture [patil 2021 infection metallomics critical care].
- Siderophore-producing Enterobacteriaceae outcompete commensals under high-iron conditions in the gut [pendergrass 2026 microbial metallomics parkinsons ferroptosis].
Iron and the Gut Microbiome
- Iron deficiency reduces commensal beneficial bacteria (Lactobacillus) while iron excess increases harmful bacteria (Bacteroides, E. coli) [bao 2024 iron homeostasis intestinal immunity gut microbiota].
- IDA reduced Bacillota abundance, increased Bacteroidota, Pseudomonadota, Patescibacteria [bao 2024 iron homeostasis intestinal immunity gut microbiota].
- Iron, manganese, and nickel availability in the gut lumen determines competitive outcomes between commensals and pathogens [pendergrass 2026 microbial metallomics parkinsons ferroptosis].
- Gut microbiota influence the host via metabolites: SCFAs (butyrate enhances epithelial barrier), indole derivatives, bile acids, and neurotransmitters (serotonin, dopamine, GABA) [bao 2024 iron homeostasis intestinal immunity gut microbiota].
Interactions with Other Metals
- Nickel disrupts iron homeostasis: Ni(II) substitutes for Fe(II) in enzyme active sites, oxidizes iron in iron-sulfur clusters, and affects IRP-1/IRP-2 regulation [salnikov 2008 metal carcinogenesis].
- Copper: Fe/Cu ratio is a sensitive cardiovascular biomarker; Cu elevation with Fe decrease in AMI [lim 2023 plasma metallomics ami]. Cu/Zn-SOD and Mn-SOD represent coordinated antioxidant defense requiring multiple metals.
- Manganese: Competes for DMT1 transport; co-exposure in welding.
- Selenium: Se and Fe cooperate in antioxidant defense (GPX4 requires both Se and iron homeostasis); Se deficiency compounds ferroptotic vulnerability.
- Cadmium: Cd accumulation is higher in iron-depleted women, potentially impairing lactoferrin-mediated antimicrobial defense [roberts 2019 lactoferrin genital infections iron].
Biomarkers
- Serum ferritin: Reflects iron stores; <1 ug associated with 3.98x PPD risk; elevated in T2D and cancer [azami 2019 anemia ppd meta analysis, khan 2014 metals type2 diabetes].
- Hemoglobin: Standard clinical marker for iron deficiency anemia.
- Hepcidin: Master regulator of iron homeostasis; positively associated with vaginal lactoferrin [roberts 2019 lactoferrin genital infections iron].
- Fe/Cu ratio: Decreased in AMI; more sensitive than individual elements; AUC 0.942 in combined model [lim 2023 plasma metallomics ami].
- Transferrin receptor (sTfR): Reflects tissue iron demand.
- Siderophore detection: Iron-acquiring metallophores as biomarkers for invasive bacterial and fungal infections [patil 2021 infection metallomics critical care].
Open Questions
- Whether ferroptosis-targeted therapies (iron chelation, GPX4 activation) can be effective across neurodegeneration, CKD, and cancer simultaneously.
- How to optimize iron supplementation to treat PPD and anemia without promoting gut dysbiosis or pathogen growth.
- The role of neuromelanin iron-binding capacity in explaining differential PD risk by MC1R genotype (redhead hypothesis).
- Whether siderophore-based diagnostics can replace or complement culture-based pathogen identification in clinical practice.
- How iron-microbiome interactions in infancy (through formula and supplementation) shape long-term health trajectories.
- Whether the Fe/Cu ratio can be validated as a clinical cardiovascular biomarker beyond the AMI setting.
Connections
- ferroptosis -- iron-dependent lipid peroxidation as convergent cell death mechanism
- nutritional immunity -- host iron sequestration as primary antimicrobial defense
- parkinsons disease -- iron accumulation in substantia nigra; ferroptotic dopaminergic neuron death
- alzheimers disease -- iron accumulation in hippocampus and cortex
- postpartum depression -- iron deficiency anemia increases PPD risk 1.89-fold
- gut microbiota -- iron status shapes commensal vs pathogen balance
- gut brain axis -- iron-microbiome-neurodegeneration link
- nickel -- Ni disrupts Fe homeostasis via enzyme active site substitution
- selenium -- cooperates with Fe in GPX4-mediated antioxidant defense
- copper -- Fe/Cu ratio as cardiovascular biomarker
- manganese -- competes for DMT1 transport
- cadmium -- increased Cd absorption in iron-depleted individuals
- thyroid autoimmunity -- iron deficiency impairs TPO activity
- Staphylococcus aureus -- elaborate iron acquisition systems to overcome nutritional immunity
- lactoferrin -- iron-binding glycoprotein central to mucosal immune defense