Galangin Attenuates Myocardial Ischemic Reperfusion-Induced Ferroptosis by Targeting Nrf2/Gpx4 Signaling Pathway

Tao Yang,1– 4 Haiqiong Liu,1,3,4 Chaobo Yang,1,3,4 Huaqiang Mo,1,3,4 Xianbao Wang,1,3,4 Xudong Song,1,3,4 Luping Jiang,2 Ping Deng,2 Ran Chen,2 Pengcui Wu,2 Aihua Chen,1,3,4 Jing Yan1,3,4 1Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Cardiovascular Medicine, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, People’s Republic of China; 3Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Jing Yan; Aihua Chen, Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, NO. 253, Gongye Avenue, Guangzhou, 510282, People’s Republic of China, Tel/Fax +86-2061643686, Email yanve1008@126.com; chenaha@126.comPurpose: Myocardial ischemic reperfusion injury (MIRI) is a crucial clinical problem globally. The molecular mechanisms of MIRI need to be fully explored to develop new therapeutic methods. Galangin (Gal), which is a natural flavonoid extracted from Alpinia Officinarum Hance and Propolis, possesses a wide range of pharmacological activities, but its effects on MIRI remain unclear. This study aimed to determine the pharmacological effects of Gal on MIRI.Methods: C57BL/6 mice underwent reperfusion for 3 h after 45 min of ischemia, and neonatal rat cardiomyocytes (NRCs) subjected to hypoxia and reoxygenation (HR) were cultured as in vivo and in vitro models. Echocardiography and TTC-Evans Blue staining were performed to evaluate the myocardial injury. Transmission electron microscope and JC-1 staining were used to validate the mitochondrial function. Additionally, Western blot detected ferroptosis markers, including Gpx4, FTH, and xCT.Results: Gal treatment alleviated cardiac myofibril damage, reduced infarction size, improved cardiac function, and prevented mitochondrial injury in mice with MIRI. Gal significantly alleviated HR-induced cell death and mitigated mitochondrial membrane potential reduction in NRCs. Furthermore, Gal significantly inhibited ferroptosis by preventing iron overload and lipid peroxidation, as well as regulating Gpx4, FTH, and xCT expression levels. Moreover, Gal up-regulated nuclear transcriptive factor Nrf2 in HR-treated NRCs. Nrf2 inhibition by Brusatol abolished the protective effect of Gal against ferroptosis.Conclusion: This study revealed that Gal alleviates myocardial ischemic reperfusion-induced ferroptosis by targeting Nrf2/Gpx4 signaling pathway.Keywords: galangin, ferroptosis, myocardial ischemia/reperfusion injury, Nrf2, Gpx4