Kaempferol protects against doxorubicin-induced myocardial damage by inhibiting mitochondrial ROS-dependent ferroptosis

Background: Doxorubicin (DOX), a widely used chemotherapeutic agent, is limited in clinical application due to its dose-dependent cardiotoxicity. Therefore, it is crucial to explore alternative therapeutic molecules or drugs for mitigating DOX-induced cardiomyopathy (DIC). In this study aimed to explore underlying mechanisms of the cardioprotective effects of Kaempferol (KP) against DIC.

Methods: H9c2 cell-based DIC model were established to explore the pharmacological mechanism. The levels of mitochondrial membrane potential, mitochondrial ROS, mitochondrial Fe²⁺ and lipid peroxidation were detected using JC-1, TMRE, Mito-SOX, Mito-Ferro Green and C11-BODIPY 581/591 probes. Furthermore, Western blot analysis measured the expression of key regulatory proteins, and NRF2-targeting siRNA was transfected into H9c2 cells. The nuclear translocation of NRF2 was assessed by immunofluorescence.

Results: Data revealed that KP mitigated DOX-induced mitochondrial damage and Ferroptosis via reducing membrane potential, mitochondrial ROS/Fe²⁺, and regulating lipid metabolism. Mechanistically, Western blot analysis revealed that KP inhibited DOX-induced Ferroptosis by activating NRF2/SLC7A11/GPX4 axis. Moreover, KP promoted the accumulation and nuclear translocation of NRF2 protein.

Conclusion: These findings demonstrated that KP protected against DOX-induced myocardial damage by inhibiting mitochondrial ROS-dependent Ferroptosis. This provides novel insights into KP as a promising drug candidate for cardioprotection.

DOX; KP; action mechanism; cardiomyocytes; cardiotoxicity; ferroptosis; mitochondrial ROS; oxidative stress.