Role of Iron in the Molecular Pathogenesis of Diseases and Therapeutic Opportunities

Abstract

Iron is an essential mineral that serves as a prosthetic group for a variety of proteins involved in vital cellular processes. The iron economy within humans is highly conserved in that there is no proper iron excretion pathway. Therefore, iron homeostasis is highly evolved to coordinate iron acquisition, storage, transport, and recycling efficiently. A disturbance in this state can result in excess iron burden in which an ensuing iron-mediated generation of reactive oxygen species imparts widespread oxidative damage to proteins, lipids, and DNA. On the contrary, problems in iron deficiency either due to genetic or nutritional causes can lead to a number of iron deficiency disorders. Iron chelation strategies have been in the works since the early 1900s, and they still remain the most viable therapeutic approach to mitigate the toxic side effects of excess iron. Intense investigations on improving the efficacy of chelation strategies while being well tolerated and accepted by patients have been a particular focus for many researchers over the past 30 years. Moreover, recent advances in our understanding on the role of iron in the pathogenesis of different diseases (both in iron overload and iron deficiency conditions) motivate the need to develop new therapeutics. We summarized recent investigations into the role of iron in health and disease conditions, iron chelation, and iron delivery strategies. Information regarding small molecule as well as macromolecular approaches and how they are employed within different disease pathogenesis such as primary and secondary iron overload diseases, cancer, diabetes, neurodegenerative diseases, infections, and in iron deficiency is provided.

Fluorescent Egg White-Based Carbon Dots as a High-Sensitivity Iron Chelator for the Therapy of Nonalcoholic Fatty Liver Disease by Iron Overload in Zebrafish

“…53 When Fe 2+ enters the cells, it is converted to the Fe 3+ ions by the divalent metal transporter 1 protein. 54 In the model of iron overload NAFLD, if Fe 3+ is used, Fe 3+ will be chelated by EWCDs in vitro and will not enter the body. Fe 2+ can transform in the blood through the gills and digestive tract of zebrafish, so we chose Fe 2+ for the construction of NAFLD by iron overload.…”

“…The iron overload model of zebrafish can be used for drug screening for diseases related to iron excess, as well as drug safety assessment. , There is a process of mutual conversion between Fe 3+ and Fe 2+ in organisms . When Fe 2+ enters the cells, it is converted to the Fe 3+ ions by the divalent metal transporter 1 protein . In the model of iron overload NAFLD, if Fe 3+ is used, Fe 3+ will be chelated by EWCDs in vitro and will not enter the body.…”

Chemically Cross-Linked Poly(β-Cyclodextrin) Particles as Promising Drug Delivery Materials

“…Deficiency or excess of Fe ions causes significant health problems in the body, e.g., having hemochromatosis can trigger some neurological diseases. Fe­(II) chelating agents are the materials that are used in the treatment of neurological diseases related to aging such as Alzheimer’s and Parkinson’s . In recent decades, many studies have been conducted to explain ferroptotic cell death, and Fe­(II) chelating agents are considered in the prevention of ferroptotic cell death .…”

“…Fe(II) chelating agents are the materials that are used in the treatment of neurological diseases related to aging such as Alzheimer's and Parkinson's. 60 In recent decades, many studies have been conducted to explain ferroptotic cell death, 61 and Fe(II) chelating agents are considered in the prevention of ferroptotic cell death. 62 Therefore, it is important to determine the chelating capacity of p(β-CD)-1 particles as they may have inhibitory effects on ferroptosis and cell death as some iron chelators prevent ferroptotic cell death.…”

Extracytoplasmic Function Sigma Factors Governing Production of the Primary Siderophores in Pathogenic Burkholderia Species

“…The transition metal iron is essential due to its involvement as a cofactor or prosthetic group in a number of key proteins such as hemoglobin, cytochromes, and iron–sulfur cluster-containing proteins ( Lawen and Lane, 2013 ). Yet excess iron is toxic due to its chemical reactivity, and improperly sequestered iron can act as a redox catalyst in the production of damaging reactive oxygen species (ROS) through its participation in the Fenton or Haber–Weiss reactions, demanding tight control on iron homeostasis ( Abbasi et al, 2021 ). Fe(II) is soluble in hypoxic, aqueous solution.…”