Protein Lactylation in Central Nervous System Diseases: Molecular Mechanisms and Targeted Therapeutic Strategies

Lactate, once considered merely a metabolic byproduct, is now recognized as a cornerstone of central nervous system (CNS) homeostasis, serving as both a vital energy substrate and signaling molecule. The identification of lysine lactylation (Kla) has established this modification as a key epigenetic link between cellular metabolism and genomic regulation. This review examines the molecular mechanisms underlying protein lactylation, including enzymatic regulation by writers, erasers, and readers as well as non-enzymatic mechanisms. The multifaceted roles of Kla are explored in the context of CNS disorders, ranging from malignancies, acute injuries, and neurodegenerative diseases. The review further examines Kla's role in neuroinflammation, metabolic reprogramming, and neuroplasticity, highlighting its potential as a sensitive biomarker. Potential therapeutic strategies are also considered, including metabolic inhibitors and nanocarriers capable of crossing the blood-brain barrier (BBB) to restore metabolic and epigenetic balance.