Iron Homeostasis and Cardiovascular Disease Risk

Iron is indispensable for oxygen transport, energy metabolism and cellular respiration, yet its levels must be tightly controlled to avoid both deficiency and toxicity. Systemic iron homeostasis relies on coordinated regulation of intestinal absorption, storage in ferritin complexes and recycling by macrophages. The liver-derived hormone hepcidin modulates iron efflux by binding to the iron exporter ferroportin, thereby orchestrating cellular iron release. Dysregulation of this axis can lead to iron overload, prompting oxidative stress, endothelial dysfunction and inflammatory activation, or to iron deficiency, exacerbating tissue hypoxia and impaired repair. Epidemiological, genetic and mechanistic studies have linked altered iron handling to a spectrum of cardiovascular disorders, including atherosclerosis, abdominal aortic aneurysm, arterial stiffness and heart failure. Emerging data underscore the dual nature of iron in vascular biology and highlight potential therapeutic avenues centred on modulation of iron availability.

Research from Nature Portfolio

Large‐scale genetic analyses have uncovered numerous genomic loci that govern key iron traits such as hepcidin concentration and soluble transferrin receptor levels. A comprehensive meta‐analysis across diverse cohorts identified over forty loci, with several newly implicated in erythropoiesis, immune response and intracellular trafficking. Mendelian randomisation of these variants revealed that inherited differences in iron status confer opposing risks: higher lifelong iron reduces anaemia‐related disorders but elevates susceptibility to genitourinary, musculoskeletal, infectious and neoplastic conditions. Complementary genome-wide association studies yielded nearly fifty additional loci associated with ferritin, transferrin saturation and total iron-binding capacity. Variants in DUOX2, F5, SLC11A2 and TMPRSS6 were shown to predispose to iron deficiency anaemia, whereas TF, HFE and TFR2 alleles associated with overload. These findings have deepened understanding of iron sensing, storage, absorption, recycling and erythropoiesis, setting the stage for precision approaches to cardiovascular risk stratification.

Iron Homeostasis and Cardiovascular Disease Risk publication trend

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

Technical terms

Hepcidin: A peptide hormone produced by the liver that controls systemic iron by inducing internalisation and degradation of ferroportin.

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

Ferritin: An intracellular protein complex that stores iron in a non-toxic form and releases it when needed.

Transferrin saturation: The ratio of serum iron to total iron-binding capacity, reflecting the proportion of transport protein occupied by iron.

Mendelian randomisation: A method using genetic variants as instrumental variables to infer causal effects of exposures (such as iron status) on disease outcomes.

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

References

1. Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm. Arteriosclerosis Thrombosis and Vascular Biology (2023).
2. Novel loci and biomedical consequences of iron homoeostasis variation. Communications Biology (2024).
3. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis. Communications Biology (2021).
4. Associations of genetically determined iron status across the phenome: A mendelian randomization study. PLOS Medicine (2019).
5. Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis. Cell & Bioscience (2020).
6. Iron Stores, Hepcidin, and Aortic Stiffness in Individuals with Hypertension. PLOS ONE (2015).