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bioRxiv · 10.64898/2026.02.19.706884

Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis

Liu, Y.·Fan, M.·Ye, Y.·Cheng, H. Y.·Sun, S.·Qiu, Z.
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Abstract

Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimers disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5xFAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of Cmpk2, a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-{beta} burden, restore synaptic plasticity, and improve cognitive function in 5xFAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.

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Liu, Y., Fan, M., Ye, Y., Cheng, H. Y., Sun, S., Qiu, Z.. 2026-02-20. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis. https://doi.org/10.64898/2026.02.19.706884

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