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

Doxorubicin (DOX) is an effective and widely used chemotherapeutic agent against various cancers. However, its clinical utility is limited by an irreversible cardiotoxicity. The underlying mechanisms of DOX-induced heart damage are complex and multifactorial, involving oxidative stress and reactive oxygen species (ROS) generation and mitochondrial dysfunction that culminate in cardiomyocyte injury and programmed cell death. Central to the cellular antioxidant defense is the nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of key antioxidant enzymes. Activation of Nrf2 enhances cellular resilience by mitigating oxidative stress and lipid peroxidation induced by DOX. Natural compounds (NCs) have shown promise in up-regulating Nrf2 and stabilizing antioxidant defenses. This review provides an update and comprehensive analysis of 51 studies published from 2020 to 2025 investigating the role of plant-derived compounds in protecting against DOX-induced cardiotoxicity through activation of Nrf2. All NCs included in this review are extracted from various plants and activate Nrf2 via multiple upstream pathways, such as Keap1-Nrf2, AMPK/Nrf2, SIRT1/Nrf2, and PI3K/AKT/Nrf2. These pathways collectively enhance antioxidant capacity, improve mitochondrial function, maintain iron homeostasis, and inhibit apoptosis and ferroptosis. The findings emphasize the diverse mechanisms through which plant-based NCs target Nrf2 signaling, highlighting their significant therapeutic potential to reduce DOX-induced cardiotoxicity.