Targeting Inhibition of Histone Lysine Demethylase Kdm5b Ameliorates Myocardial Ischemia-Reperfusion Injury by Restoring Brinp2 Expression

While reactive oxygen species (ROS) overproduction is a central pathogenic event, direct antioxidant strategies have largely failed clinically. Epigenetic regulation, particularly histone methylation, has emerged as a critical player in cardiac stress responses, yet the role of specific histone demethylases in I/R remains largely unexplored.

Here, we identify lysine-specific demethylase 5B (Kdm5b), an eraser of the active transcription mark H3K4me3, as a key pathogenic mediator and therapeutic target in myocardial I/R injury. Kdm5b is markedly upregulated in hypoxic cardiomyocytes, leading to reduced H3K4me3 levels. Pharmacological inhibition of Kdm5b with AS8351, or genetic knockdown, protects cardiomyocytes from hypoxia/reoxygenation-induced (H/R) cell death, oxidative stress, and mitochondrial dysfunction.