Flipping the Switch: MeCP2-Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2/mTOR Axis in Poststroke Neuroinflammation

Microglial metabolic/inflammatory reprogramming critically influences stroke outcomes, yet its mechanisms remain poorly understood. Lysine lactylation, an epigenetic modification in which lactate-derived lactyl groups modify lysine residues, regulates immune and neurological processes. Here, lysine lactylation is identified as a key link between ischemic metabolic stress and microglial dysfunction. Stroke-induced lactate accumulation drives microglial protein lactylation, which correlates with poor neurological outcomes. Proteomics identified that methyl-CpG binding protein 2 (MeCP2) is lactylated at lysine 210 (K210), enhancing its transcriptional activation of glycolytic/inflammatory genes, especially Hexokinase 2 (HK2). HK2 overexpression mimics lactylation-induced pathology (mitochondrial dysfunction, glycolytic shift, inflammation), while knockdown reverses these effects. Lactylated MeCP2 impairs mitochondrial respiration, disrupts metabolic signaling (leading to dysregulated activation of the mammalian target of rapamycin (mTOR)/AMPK pathway), and sustains neuroinflammation. Genetic ablation of MeCP2-K210 lactylation (via K210R mutation), pharmacological inhibition of lactyltransferase p300, or HK2 inhibition with lonidamine restores mitochondrial function, attenuates neuroinflammation, and improves neurofunctional recovery. The findings establish MeCP2-K210 lactylation as a critical metabolic-epigenetic switch driving microglial activation via the HK2/mTOR axis, identifying a therapeutic target for postischemic neuroinflammation.

MeCP2; ischemic stroke; lactylation; microglia; neuroinflammation.