Targeting inhibition of histone lysine demethylase KDM5B ameliorates myocardial ischemia-reperfusion injury by restoring Brinp2 expression.

Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge with limited effective therapies, largely due to incomplete mechanistic understanding. 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 H3K4me3 demethylase, 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 of KDM5B, protects cardiomyocytes from hypoxia/reoxygenation-induced (H/R) cell death, oxidative stress, and mitochondrial dysfunction. In mice, post-reperfusion AS8351 administration improves cardiac function and reduces infarct size. Integrative transcriptomic and epigenomic analyses identify Brinp2 as a direct transcriptional target of KDM5B. KDM5B occupies the Brinp2 locus, and its inhibition restores H3K4me3 occupancy and Brinp2 expression. BRINP2 partially localizes to mitochondria, and its overexpression is sufficient to enhance ATP production while suppressing ROS. Conversely, Brinp2 knockdown impairs mitochondrial function and autophagic flux, and largely abolishes AS8351-mediated protection both in vitro and in vivo. Collectively, our findings reveal a KDM5B-H3K4me3-BRINP2 epigenetic axis governing cardiomyocyte survival during I/R stress and identify KDM5B as a promising therapeutic target for ischemic heart disease.