SEARCHNARRATIVE_REVIEWophthalmology, neurology

narrative_review·ophthalmology, neurology, endocrinology, oncology, immunology·PMC10045916

Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target

Antioxidants · 2 authors, 2 centres

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TL;DR

Iron dysregulation, leading to excess reactive iron, is a common underlying factor in a wide range of diseases including infections, cancer, inflammatory, neurological, and metabolic conditions. This review highlights the potential of new iron chelators and hepcidin agonists as promising therapeutic strategies to restore iron homeostasis. The clinical significance lies in the broad applicability of targeting iron dysregulation across diverse pathologies, offering a novel avenue for treatment.

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**Background:** Iron is essential for numerous biological processes, including energy production, nucleic acid synthesis, and cellular defense, but it becomes toxic when present in excess due to its ability to generate reactive oxygen species (ROS) via redox cycling. The body tightly regulates iron homeostasis through mechanisms such as transferrin chaperoning and hepcidin-mediated control of ferroportin. Dysregulation of this system leads to elevated levels of labile reactive iron, which is implicated in the pathogenesis of various diseases. This review explores the role of iron dysregulation in diverse conditions and evaluates emerging therapeutic approaches.

**Methods:** This is a narrative review that synthesizes evidence from a wide range of studies on iron biology, iron dysregulation in disease, and potential therapies. The authors discuss biological iron requirements, normal regulation, and the nature of iron dysregulation in infections, cancer, ferroptosis, inflammatory diseases (ocular, lung fibrosis, kidney), diabetes, cardiovascular disease, autoimmune conditions, neurological disorders, iron overload, cirrhosis, and anemia of chronic disease. They also review therapeutic options including iron restriction, iron chelators, and hepcidin agonists, drawing on clinical trial data and preclinical studies.

**Key Results:** The review identifies that iron dysregulation is characterized by elevated transferrin-bound iron (TBI) with transferrin saturation above normal 30%, sometimes reaching 100%, and the presence of non-transferrin-bound iron (NTBI) labile reactive iron (LPI). This excess iron supports proliferative diseases like infections and cancer by providing iron to pathogens or cancer cells, and drives toxicity in metabolic, neurological, and inflammatory diseases through ROS production and ferroptosis. Specific examples include: in sepsis, high serum iron levels are associated with poor outcomes, with transferrin saturation strongly correlated to lethality; in cancer, higher transferrin saturation levels were linked to increased risk in a cohort of 14,000 participants; in ocular diseases, ferroptosis is implicated in conditions like age-related macular degeneration (AMD) and cataracts; in diabetes, dysregulated iron metabolism with increased serum ferritin is found in newly diagnosed type 2 diabetes; in neurological diseases, iron accumulation is seen in Parkinson's disease and Alzheimer's disease. Current therapeutic options include iron chelators like deferoxamine, which can fully coordinate iron, but existing chelators have limitations. New purpose-designed chelators and hepcidin agonists (e.g., VIT-2763, rusfertide) show promise in early clinical trials, with VIT-2763 advancing to phase II and rusfertide showing promising phase III results.

**Clinical Implications:** The review underscores that targeting iron dysregulation offers a broad therapeutic avenue for multiple diseases. Improved iron chelators that effectively sequester labile reactive iron could treat infections (including sepsis), cancer, and non-proliferative diseases. Hepcidin mimetics and ferroportin inhibitors also show potential for lowering serum iron levels. However, careful consideration is needed to avoid triggering anemia, and further research is required to understand the mechanisms of iron dysregulation in various diseases, particularly the anemia of chronic disease and ferroptosis in cancer.

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narrative_review

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ophthalmology

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ORIGINAL PAPER

PMC10045916

Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target

Antioxidants

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ABSTRACT

Iron is irreplaceably required for animal and human cells as it provides the activity center for a wide variety of essential enzymes needed for energy production, nucleic acid synthesis, carbon metabolism and cellular defense. However, iron is toxic when present in excess and its uptake and storage must, therefore, be tightly regulated to avoid damage. A growing body of evidence indicates that iron dysregulation leading to excess quantities of free reactive iron is responsible for a wide range of otherwise discrete diseases. Iron excess can promote proliferative diseases such as infections and cancer by supplying iron to pathogens or cancer cells. Toxicity from reactive iron plays roles in the pathogenesis of various metabolic, neurological and inflammatory diseases. Interestingly, a common underlying aspect of these conditions is availability of excess reactive iron. This underpinning aspect provides a potential new therapeutic avenue. Existing hematologically used iron chelators to take up excess iron have shown serious limitations for use but new purpose-designed chelators in development show promise for suppressing microbial pathogen and cancer cell growth, and also for relieving iron-induced toxicity in neurological and other diseases. Hepcidin and hepcidin agonists are also showing promise for relieving iron dysregulation. Harnessing iron-driven reactive oxygen species (ROS) generation with ferroptosis has shown promise for selective destruction of cancer cells. We review biological iron requirements, iron regulation and the nature of iron dysregulation in various diseases. Current results pertaining to potential new therapies are also reviewed.

CITATION EXPORT

Bruce E. Holbein, Christian Lehmann. Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target. Antioxidants. (2023). https://doi.org/10.3390/antiox12030671

AUTHORS

2 · 2 CENTRES

Bruce E. Holbein, Christian Lehmann

1Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 1X5, Canada
2Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 1X5, Canada

EDITOR / REVIEWER

Yan-Zhong Chang