Inhibition of KDM5A alleviates ferroptosis in myocardial infarction via the GDF15-GPX4 axis

Myocardial infarction (MI) is an acute cardiovascular condition with a poor prognosis, imposing substantial disease and economic burdens worldwide. The histone demethylase KDM5A is known to respond to oxygen levels; however, its role in MI remains unclear. Ferroptosis plays a decisive role in myocardial injury; however, whether it is regulated by KDM5A epigenetically remains unknown. Here, we established an MI mouse model via left anterior descending coronary artery ligation and a hypoxic HL-1 cardiomyocyte model. Cardiac function, infarct size, and ferroptosis markers (Fe²⁺ and MDA) were assessed following KDM5A pharmacological inhibition or genetic manipulation. Epigenetic mechanisms were investigated using Cut&Tag, qPCR, and Western blot assays. The results reveal that KDM5A promotes ferroptosis and aggravates cardiac injury. Inhibition of KDM5A significantly alleviates infarct damage. Cut&Tag analysis indicates that KDM5A bound to the Gdf15 promoter, thereby removing H3K4me3 and suppressing Gdf15 transcription. These changes result in the downregulation of glutathione peroxidase 4 (GPX4) and enhance ferroptosis. These findings suggest that KDM5A drives cardiomyocyte ferroptosis through the GDF15-GPX4 axis. This study identifies KDM5A as an epigenetic regulator of ferroptosis and a promising therapeutic target for MI.