GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328862/primaryOK200GenomicsRattus norvegicusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328862GEOGSEfalseTargeting Inhibition of Histone Lysine Demethylase Kdm5b Ameliorates Myocardial Ischemia-Reperfusion Injury by Restoring Brinp2 ExpressionMyocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge lacking 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 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. 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. Notably, Brinp2 knockdown largely abolishes AS8351-mediated protection both in vitro and in vivo. Collectively, our findings reveal a previously unrecognized Kdm5b-H3K4me3- Brinp2 epigenetic axis governing cardiomyocyte survival during I/R stress and position Kdm5b as a promising therapeutic target for ischemic heart disease.2026/07/27GSE328862GSM9691126GSM9691125GSM9691124GSM969112325947328862Rattus norvegicus