Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target

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.

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials

“…Essential for cellular functions, iron in excess can lead to diseases. Dysregulated iron, associated with conditions like infections and cancer, promotes the development of purpose-designed chelators and hepcidin agonists as potential therapies, with a focus on cancer cells through iron-driven reactive oxygen species generation with ferroptosis, providing a novel therapeutic avenue [28]. Elevated iron levels are detected in ovarian cancer [29], breast cancer [30], and liver cancer [31].…”

The Beneficial Impact of Iron-Fortified Complementary Feeding in the Burden of Iron Deficiency Anaemia (IDA) in Children of Bangladesh

“…Ascorbic acid has a direct correlation with the absorption of ferric iron during meals because it activates the duodenal ferric reductase [35]. [33].…”

Susceptibility of acute myeloid leukemia cells to ferroptosis and evasion strategies

“…Iron is an essential trace element involved in many physiological activities in the human body, is extremely oxidizing, generates excess ROS through the Fenton reaction, and is an important cofactor involved in the synthesis of enzymes responsible for lipid peroxidation and oxygen homeostasis ( Holbein and Lehmann, 2023 ). Iron is usually bound to a complex such as heme (a prosthesis of numerous proteins such as hemoglobin), iron-sulfur clusters (a cofactor for many enzymes), or ferritin (a specialized iron storage protein) ( Stockwell, 2022 ).…”