Lactylation in the ageing nervous system: Epi-metabolic regulation, disease mechanisms, and translational challenges

Lactate was long considered a waste metabolic byproduct. Currently, lactate functions as an energy substrate, signaling molecule, and epigenetic regulator in the central nervous system (CNS). Lysine lactylation (Kla), a novel lactate-dependent PTM, acts as a core epi-metabolic mediator by directly linking cellular metabolism to epigenetic remodeling. This review summarizes lactate production, shuttling, and the regulatory mechanism of lactylation (donors, writers, erasers, readers). We outline the multifaceted functions of lactylation in neurodevelopment, synaptic plasticity, and neural energy homeostasis, alongside its pathological dysregulation in major neurological disorders, with particular emphasis on ageing-related conditions. We further discuss the interplay between aberrant Kla and core ageing hallmarks, including mitochondrial dysfunction, impaired proteostasis, and inflammageing. Kla exerts site‑specific, cell‑type‑specific, and context‑dependent effects that are either protective or pathological. We also discuss therapeutic strategies targeting lactate metabolism and lactylation-modifying enzymes, analyzing the translational challenges involved. This review suggests Kla as an emerging epi-metabolic target that merits further investigation for therapeutic interventions in the ageing nervous system.