Page 24 - G. Cell differentiation. division. and death

[G. Cell differentiation, division, and death-17]

Identification of natural compound inhibitors of ferroptosis

in cardiomyocytes

Jeong Eun Lee¹˙², Kwang-Hee Bae¹˙², Sang Chul Lee¹˙², Eun-Woo Lee¹

¹Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon

34141, Korea, ²Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141,
Korea

Cardiomyocyte death during myocardial infarction (MI) plays a key role in cardiac damage and heart failure. Recently,

it has been reported that ferroptosis, an iron-dependent non-apoptotic cell death, contributes to myocardial cell

death during MI. Therefore, ferroptosis inhibitors are expected as potential drugs for heart failure. In this study, we
investigated natural compounds for their potential as ferroptosis inhibitors using natural products library which
contains about 658 single compounds. To test this, ferroptosis was induced by the treatment with glutathione

peroxidase 4 (GPX4) inhibitor RSL3 in the presence of natural compounds in H9c2 cardiomyoblasts and cell viability
were measured. As a result, we found several natural compounds, which significantly inhibited ferroptosis induced

by GPX4 inhibition or cysteine deprivation. Since lipid peroxidation is a hallmark of ferroptosis, the levels of lipid
peroxide were determined by flow cytometry using the fluorescent probe C11-BODIPY. Furthermore, several

compounds did not inhibit H2O2-induced cell death, implying that these compounds might not be general
antioxidant. In summary, our data identify several natural compounds as novel ferroptosis inhibitors in

cardiomyocytes and potential therapeutic agents against MI.