Carvedilol Confers Ferroptosis Resistance in HL-1 Cells by Upregulating GPX4, FTH1, and FTL1 and Inducing Metabolic Remodeling Under Hypoxia/Reoxygenation

Hypoxia/reoxygenation (HR) often occurs under cardiac pathological conditions, and HR-induced oxidative stress usually leads to cardiomyocyte damage. Carvedilol, a non-selective β-blocker, is used clinically to treat cardiac ischemia diseases. Moreover, Carvedilol has also been reported to have an antioxidant ability by reducing lipid peroxidation. However, the mechanism of Carvedilol to inhibit lipid peroxidation is still elusive. To explore the protective mechanism of Carvedilol to resist lipid peroxidation on cardiomyocytes, HL-1 cells were cultured under normoxia, hypoxia, and HR and treated with Carvedilol to investigate the alteration on metabolism, protein expression, and mRNA level to explain its oxidative mechanism. The study found that Carvedilol upregulated glutathione peroxidase 4 (GPX4) protein expression to resist HR-induced lipid peroxidation by metabolic remodeling under HR. Also, Carvedilol promoted ferroptosis-related genes, ferritin heavy chain 1 (<i>FTH1</i>) and ferritin light chain 1 (<i>FTL1</i>) mRNA levels, to reduce lipid peroxidation under both hypoxia and HR. In conclusion, our study explores a mechanism by which Carvedilol inhibits ferroptosis by upregulating GPX4, <i>FTH1</i>, and <i>FTL1</i> levels to downregulate lipid peroxidation under HR. The study provides a potential strategy for using Carvedilol in clinical applications, inspiring further research and development in the area of heart diseases.