ACLY alleviates cerebral ischemia/reperfusion injury by reducing oxidative stress and enhancing mitochondrial...

Cell metabolism and epigenetic regulation play crucial roles in modulating cerebral ischemia/reperfusion (I/R) injury. How cell metabolism regulates cerebral I/R injury by regulating epigenetic modifications remains unclear. In this study, we utilized an in vivo injury model of transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. The middle cerebral artery was occluded for 90 min, followed by reperfusion at different time points. We observed that the expression of ATP-citrate lyase (ACLY), an important enzyme involved in lipid synthesis, was significantly upregulated under cerebral I/R conditions. Inhibition of ACLY markedly exacerbated cerebral I/R injury in vivo. ACLY inhibition and knockdown in vitro also reduced cell viability in cultured neurons following oxygen-glucose deprivation/reoxygenation (OGD/R). Mechanistic studies revealed that ACLY enhances histone acetylation at the promoter regions of mitochondrial respiratory chain complexes by facilitating the accumulation of acetyl-CoA, thereby improving mitochondrial function and attenuating oxidative stress. Our findings reveal a novel metabolic-epigenetic axis mediated by ACLY in the regulation of cerebral I/R injury which may serve as a potential target for therapeutic intervention in ischemic stroke.