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

## TL;DR

This study shows that inhibiting HDAC1/2 in microglia after brain hemorrhage reduces inflammation and improves brain recovery by changing energy metabolism.

## Contribution

The study reveals a novel role of HDAC1/2 in regulating microglial metabolism and function through HK2 acetylation after intracerebral hemorrhage.

## Key findings

- HDAC1/2 inhibition reduces HK2 acetylation and shifts microglial metabolism from glycolysis to fatty acid oxidation.
- This metabolic shift reduces pro-inflammatory responses and enhances phagocytic activity in microglia.
- HDAC1/2 inhibition also promotes mitophagy and reduces microglial proliferation and cell numbers.

## 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.

This study demonstrates that HDAC1/2 knockout in microglia alleviates neurological deficits, preserves white matter, and accelerates hematoma clearance after ICH. HDAC1/2 inhibition reduces HK2 acetylation, shifts metabolism from glycolysis to fatty acid oxidation, reduces inflammation, and enhances phagocytosis. However, it also impairs mitochondrial function, promotes mitophagy, and reduces microglial proliferation, leading to fewer microglial cells. These findings highlight the role of HDAC1/2 in regulating microglial function and metabolism post‐ICH.