Flavonoids Ameliorate Ferroptotic Cell Death in Cardiomyocytes through ROS Scavenging and Lipid Peroxide Reduction

Myocardial ischemia-reperfusion injury (MIRI) is a lethal disease that occurs after percutaneous intervention which may lead acute myocardial infarction patients to heart failure. Therefore, it is an important issue to find solutions for MIRI. A newly discovered cell death named ferroptosis has been associated with MIRI. Ferroptosis, which is characterized by iron-dependent accumulation of lipid peroxide is distinct from necrosis and apoptosis. Lipophilic antioxidants like ferrostatin-1 have been discovered to inhibit ferroptosis effectively. Flavanoids, such as Fisetin and Kaempferol (KMP), are natural compounds that are found in many edible plants. They are lipophilic antioxidants that show cardio-protective effects through scavenging ROS, inhibiting inflammation in MIRI models. However, the effect of flavonoids in inhibiting ferroptosis associated with MIRI remains unclear. This study investigated the ability of Fisetin and KMP to attenuate ferroptosis in H9c2 cells. H9c2 cells were treated with ferroptosis inducers erastin, RSL3, and Fe-SP. Fisetin and KMP could protect cells against ferroptosis caused by these ferroptosis inducers by ROS scavenging, lipid peroxide reduction, and decrease the mRNA levels of the ferroptosis marker Ptgs2. Thus, Fisetin and KMP play a protective role in H9c2 cells against ferroptosis which may be an effective candidate to treat MIRI.