From metabolic substrate to epigenetic regulation: roles and mechanisms of lactylation in brain health and disease.
This review argues that lactate-driven protein lactylation links metabolism to epigenetic regulation in the brain, influencing synaptic plasticity and neuroinflammation and implicating the lactate–lactylation axis in Parkinson's disease pathophysiology.
What the AI sees
This review argues that lactate-driven protein lactylation links metabolism to epigenetic regulation in the brain, influencing synaptic plasticity and neuroinflammation and implicating the lactate–lactylation axis in Parkinson's disease pathophysiology.
Research significance
Highlights lactylation as a novel, potentially drug‑targetable mechanism and source of biomarkers that ties metabolic dysfunction to neuroinflammation in PD, offering a promising but still early-stage avenue for therapeutic and diagnostic development.
Source abstract
Lactate, traditionally regarded as a metabolic byproduct of glycolysis, is now recognized as a critical signaling molecule in the central nervous system. Emerging evidence indicates that lactate participates in a dynamic metabolic-epigenetic regulatory network through protein lactylation, a post-translational modification capable of modulating chromatin structure and gene transcription. We summarize the physiological roles of lactate in neuronal-glial metabolic coupling and highlight cell-type-specific functions of the lactate-lactylation axis under both normal and pathological conditions. Particular emphasis is placed on its involvement in ischemic stroke, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Available findings indicate that this axis is integral to synaptic plasticity, neuroinflammatory balance, and metabolic homeostasis. Under pathological conditions, excessive lactate accumulation promotes aberrant lactylation patterns that may drive persistent inflammation, metabolic reprogramming, and neuronal dysfunction by reshaping chromatin accessibility and transcriptional landscapes. Collectively, the lactate-lactylation axis represents a unifying mechanistic framework linking metabolic flux to epigenetic regulation in neurological disorders and may serve as a promising source of diagnostic biomarkers and precision therapeutic targets.