An Updated Overview on Targeting Nrf2 by Natural Compounds Against Doxorubicin-Induced Cardiotoxicity.

Area of Science:

• Cardiology
• Pharmacology
• Biochemistry

Background:

• Doxorubicin (DOX) is a vital chemotherapy drug, but its use is limited by severe cardiotoxicity.
• DOX-induced heart damage involves oxidative stress, mitochondrial dysfunction, and cardiomyocyte death.
• Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial for cellular antioxidant defense against DOX.

Purpose of the Study:

• To review recent studies (2020-2025) on plant-derived natural compounds (NCs) that protect against DOX-induced cardiotoxicity.
• To analyze the mechanisms by which NCs activate the Nrf2 pathway.
• To highlight the therapeutic potential of NCs in mitigating chemotherapy side effects.

Main Methods:

• Comprehensive literature review of 51 studies published between 2020 and 2025.
• Analysis of studies investigating plant-derived compounds and their effect on Nrf2 activation.
• Examination of upstream pathways (Keap1-Nrf2, AMPK/Nrf2, SIRT1/Nrf2, PI3K/AKT/Nrf2) involved in Nrf2 signaling.

Main Results:

• Plant-derived NCs effectively activate Nrf2 signaling through various upstream pathways.
• Nrf2 activation by NCs enhances antioxidant capacity and improves mitochondrial function.
• NCs mitigate DOX-induced cardiotoxicity by inhibiting apoptosis and ferroptosis and maintaining iron homeostasis.

Conclusions:

• Plant-derived natural compounds show significant promise in preventing Doxorubicin-induced cardiotoxicity.
• Targeting the Nrf2 pathway with natural compounds offers a potential strategy to reduce chemotherapy-related heart damage.
• Further research into these NCs could lead to novel therapeutic interventions for cancer patients.