Zhang Lin, Liu Xiaorui, Wang Juan, Li Zimu, Wang Siqi, Yang Wen, Hai Yang, Liu Dongling
School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People's Republic of China.
Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou, People's Republic of China.
Redox Rep. 2025 Dec;30(1):2503130. doi: 10.1080/13510002.2025.2503130. Epub 2025 May 13.
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.
H9c2 cell-based DIC model were established to explore the pharmacological mechanism. The levels of mitochondrial membrane potential, mitochondrial ROS, mitochondrial Fe 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.
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.
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.
阿霉素（DOX）是一种广泛使用的化疗药物，由于其剂量依赖性心脏毒性，在临床应用中受到限制。因此，探索替代治疗分子或药物以减轻阿霉素诱导的心肌病（DIC）至关重要。本研究旨在探讨山奈酚（KP）对DIC心脏保护作用的潜在机制。
建立基于H9c2细胞的DIC模型以探索其药理机制。使用JC-1、TMRE、Mito-SOX、Mito-Ferro Green和C11-BODIPY 581/591探针检测线粒体膜电位、线粒体ROS、线粒体铁和脂质过氧化水平。此外，蛋白质免疫印迹分析测定关键调节蛋白的表达，并将靶向NRF2的小干扰RNA转染到H9c2细胞中。通过免疫荧光评估NRF2的核转位。
数据显示，KP通过降低膜电位、线粒体ROS/Fe²以及调节脂质代谢减轻了DOX诱导的线粒体损伤和铁死亡。机制上，蛋白质免疫印迹分析显示，KP通过激活NRF2/SLC7A11/GPX4轴抑制DOX诱导的铁死亡。此外，KP促进了NRF2蛋白的积累和核转位。
这些发现表明，KP通过抑制线粒体ROS依赖性铁死亡保护心脏免受DOX诱导的心肌损伤。这为KP作为一种有前景的心脏保护药物候选物提供了新的见解。
