Decreasing H3K27me3 alleviates cerebral ischemia/reperfusion injury by modulating FOXP1 expression

Abstract

Elevated H3K27me3 levels during cerebral I/R injury exacerbate neuronal damage through oxidative stress, but the underlying mechanism remains to be elucidated. We hypothesized that reduced H3K27me3 confers protection by modulating FOXP1 expression. Employing multifaceted approaches, we demonstrate that H3K27me3 reduction in vivo and in vitro enhances lipid metabolism and rescues oxygen-glucose deprivation (OGD)-induced mitochondrial morphological abnormalities and functional deficits. Furthermore, chromatin immunoprecipitation sequencing analysis revealed that H3K27me3 directly targets FOXP1, a member in the negative regulation of intracellular steroid signal pathway. Further study suggested that genetic knockdown of FOXP1 abolished the protective effects of H3K27me3 reduction against I/R injury. Collectively, our findings establish H3K27me3-dependent FOXP1 repression as a central mechanism driving lipid metabolic dysregulation and mitochondrial dysfunction in cerebral I/R pathogenesis, revealing novel therapeutic targets.