HDAC1 K438 Lactylation is Associated with NF-κB-related Microglial Inflammatory Activation in Alzheimer’s Disease

Abstract Alzheimer’s disease (AD) is characterized by persistent microglial activation, yet how metabolic stress contributes to inflammatory reprogramming remains unclear. This study investigated the role of histone deacetylase 1 (HDAC1) lactylation in microglial inflammation. HDAC1 and global protein lactylation were examined in human AD prefrontal cortex and 5×FAD mice, alongside human single-nucleus and spatial transcriptomic analyses. Proteomic and lactylomic profiling of BV2 microglia exposed to hypoxia and lipopolysaccharide (LPS-Hy) was used to characterize inflammatory reprogramming and identify candidate HDAC1 lactylation sites, followed by molecular docking and mutagenesis. HDAC1 lactylation and global protein lactylation signals were elevated in IBA1-positive microglia in human AD tissue and 5×FAD mice and associated with activation markers. Transcriptomic analyses revealed no corresponding increase in HDAC1 mRNA in AD microglia, implicating post-translational modification in HDAC1-associated inflammatory regulation. Lactylomic profiling identified K438 as a major HDAC1 lactylation site, while molecular docking suggested structural compatibility between lactate and the HDAC1 catalytic pocket. Wild-type HDAC1 enhanced LPS-Hy-induced Il1b and Nos2 expression, whereas the K438R mutant abolished detectable HDAC1 lactylation and lost this enhancing effect, accompanied by altered total p65 abundance. Cross-dataset integration identified a conserved immune–metabolic microglial module across human AD, Aβ-positive microglia, and LPS-Hy-treated BV2 cells, with HDAC1 as a highly connected network hub. Together, these findings support a role for HDAC1 K438 lactylation in regulating microglial inflammatory responses under metabolic and inflammatory stress, highlighting a potential non-histone post-translational mechanism linking cellular stress to immune-metabolic reprogramming and a candidate target for further investigation in AD.