Disengaging the Engine: Histone Deacetylases 1 and 2‐Mediated Acetylation of Hexokinase‐2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage

ABSTRACT Microglia‐mediated neuroinflammation is closely associated with the pathogenesis of secondary brain injury following spontaneous intracerebral hemorrhage (ICH). However, the relationship between immune response regulation and metabolic patterns in microglia remains unclear. Histone Deacetylases 1 and 2, a class of lysine deacetylases, regulates gene transcription by modulating histone acetylation modifications and is widely involved in various cellular activities of microglia. In this study, we observed that knockout of HDAC1/2 in microglia alleviated neurological deficits caused by ICH, preserved white matter integrity, and accelerated hematoma clearance post‐ICH. Mechanistically, we found that after ICH, microglia exhibited increased expression of hexokinase 2 (HK2) and enhanced glycolysis. HDAC1/2 knockout/pharmacological inhibition affected the acetylation level of HK2, inhibited its glycolytic activity, and promoted a metabolic shift in activated microglia from glycolysis to fatty acid oxidation. This shift was associated with reduced pro‐inflammatory responses and enhanced phagocytic activity in microglia. Enhanced fatty acid oxidation may have a detrimental effect on mitochondrial function, and HDAC1/2 inhibition simultaneously promoted mitophagy in microglia. Additionally, HDAC1/2 inhibition triggered microglial apoptosis and suppressed proliferation, ultimately leading to a reduction in microglial cell numbers. Overall, this study reveals the potential mechanisms by which targeting HDAC1/2, through acetylation modifications and transcriptional regulation, modulates microglial function and metabolism after ICH, thereby exerting protective effects.