Nrf2 activators for the treatment of rare iron overload diseases: From bench to bedside

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Rare diseases often involve iron overload and oxidative damage due to genetic mutations affecting iron homeostasis.
• Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates cellular antioxidant responses and can lower iron levels by influencing iron-related genes and pathways.

Purpose of the Study:

• To explore the therapeutic potential, mechanisms, and precautions of Nrf2 activators for rare iron overload disorders.
• To propose combination therapy with Nrf2 activators and iron chelators for enhanced clinical application.

Main Methods:

• Literature review on Nrf2 activators and iron overload disorders.
• Analysis of Nrf2-mediated pathways involved in iron regulation and oxidative stress.
• Evaluation of existing clinical examples and proposed combination strategies.

Main Results:

• Nrf2 activators are effective in managing iron overload and oxidative damage in certain rare diseases.
• Omaveloxolone and dimethyl fumarate serve as successful examples of Nrf2 activator therapy.
• Potential for Nrf2 activators in treating a broader range of iron overload disorders is significant but potentially overlooked.

Conclusions:

• Nrf2 activators represent a promising therapeutic strategy for rare iron overload diseases.
• Further research and clinical application of Nrf2 activators, potentially in combination with iron chelators, are warranted.
• This approach could significantly benefit patients with various iron overload conditions.