Role of glycolysis-mediated histone lactylation in microglial activation and progression of neurodegenerative diseases.

Microglia-mediated neuroinflammation is a key driver of neurodegenerative disease progression, yet the metabolic mechanisms underlying microglial dysfunction remain poorly understood. Recent studies highlight glycolytic reprogramming in activated microglia, which generates lactate that, in turn, promotes histone lactylation, an epigenetic modification that significantly alters gene expression. This glycolysis-histone lactylation axis has been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, where its dysregulation exacerbates chronic neuroinflammation and neuronal damage. Despite this, the precise molecular mechanisms linking microglial metabolic shifts to epigenetic remodeling and disease pathogenesis are not fully defined. This review consolidates current knowledge on how the glycolysis-histone lactylation pathway influences microglial phenotypes and function in neurodegenerative contexts. We explore the molecular machinery driving lactate-mediated histone modifications, their transcriptional consequences, and their pathological impact on disease progression. Importantly, we discuss emerging therapeutic strategies targeting this metabolic-epigenetic axis, including glycolysis inhibitors and lactylation modulators, as promising precision medicine approaches for neurodegenerative diseases. By elucidating these mechanisms, this review provides a framework for developing metabolism-based interventions aimed at restoring microglial homeostasis and slowing neurodegeneration.