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

Fatemeh Yarmohammadi1,2, Gholamreza Karimi3,4

  • 1Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.

Phytotherapy Research : PTR
|April 28, 2026
PubMed

Insights

Natural compounds activate the Nrf2 pathway to protect the heart from Doxorubicin (DOX) chemotherapy. This review highlights plant-derived compounds that mitigate DOX-induced cardiotoxicity by enhancing antioxidant defenses.

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.
Keywords:
Keap1antioxidantferroptosismyocardial toxicityoxidative stress

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