The technical foundation of this story lies in how the brain handles carbon and energy. Neurons are voracious consumers of glucose, and under aerobic conditions glycolysis converts glucose to pyruvate, which is then imported into mitochondria and oxidized by the tricarboxylic acid cycle. When oxygen is scarce or demand outpaces oxidative capacity, lactate dehydrogenase converts pyruvate to lactate, regenerating NAD+ so glycolysis can continue. In the brain, this is not merely an emergency fallback. The astrocyte-neuron lactate shuttle describes a division of labor in which astrocytes, which take up glucose and glutamate from the synaptic environment, export lactate through monocarboxylate transporters for neurons to oxidize as fuel. A complementary intracellular lactate shuttle moves lactate into mitochondria via mitochondrial monocarboxylate transporters, where it can be reconverted to pyruvate and fed into oxidative phosphorylation. The result is a metabolically flexible network in which lactate flows between cell types and compartments as both fuel and signal.

What transformed lactate from fuel to regulator was the discovery in 2019 that lactate can covalently modify lysine residues on histones—the proteins around which DNA is wound—in a reaction termed lactylation. Histone lactylation requires lactyl-coenzyme A as the acyl-donor, and the addition of a lactyl group to lysine residues alters chromatin accessibility, generally opening DNA and promoting gene transcription. This places lactylation alongside acetylation and methylation as an epigenetic mark, but with a crucial difference: its abundance tracks directly with metabolic state. When glycolysis is high and lactate accumulates, lactylation rises; when lactate falls, the mark recedes. Metabolism is thereby coupled to gene expression through a single chemical handle, and the review emphasizes that this coupling is now being mapped in detail across the nervous system.

In neural stem cells and neural progenitor cells, histone lactylation appears to be a molecular throttle on the decision to proliferate and differentiate. The review describes evidence that elevated lactate promotes the expression of genes associated with neural stem cell proliferation and neuronal maturation, including activity-regulated cytoskeletal-associated protein and brain-derived neurotrophic factor, through lactylation-driven epigenetic activation. In the adult brain, neurogenesis persists in two niches: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone lining the lateral ventricles. Adult hippocampal neurogenesis, in particular, underpins learning, memory, and mood regulation, and markers such as doublecortin flag the newborn neurons it produces. By linking glycolytic flux to the chromatin state of neural stem cells, lactylation provides a mechanism by which the metabolic environment of the niche—oxygen tension, vascular supply, inflammatory tone—can be translated into instructions about whether progenitors stay quiescent, divide, or commit to a neuronal fate.

Lactylation is not confined to histones. Non-histone proteins, including enzymes, structural proteins, and signaling molecules, carry lysine lactylation marks that can alter their activity, stability, localization, or interaction partners. The review highlights that non-histone lactylation regulates specific protein functions in ways that extend the modification’s influence well beyond gene regulation, though the precise functional consequences at individual sites remain an active area of investigation. Because lactylation, like acetylation, adds a bulky, negatively charged group to lysine, it can compete with or mimic other modifications, creating a dense regulatory cross-talk in which metabolic state reshapes the entire post-translational modification landscape of a cell.

The protective face of lactate in the nervous system rests on three pillars described in the review. First, lactate is an efficient energy substrate for neurons, and supporting neuronal metabolism can buffer cells against the energetic stress that accompanies aging and disease. Second, lactate signaling promotes neurotrophic effects: lactate can stimulate vascular endothelial growth factor A production, supporting the vascular niche that nourishes neural progenitors, and it engages hydroxycarboxylic acid receptor 1, a G-protein-coupled receptor that mediates anti-inflammatory signaling. Third, lactate can dampen neuroinflammation. In models of activated immune cells, elevated lactate has been shown to shift macrophage and microglial behavior toward less inflammatory phenotypes, in part through lactylation-dependent and HCAR1-dependent pathways. In the context of neurodegeneration, where chronic inflammation and mitochondrial dysfunction are hallmarks, these mechanisms suggest that boosting lactate availability or lactylation could, in principle, slow neuronal loss.

The toxic face emerges when the same chemistry is applied in the wrong context. The review is explicit that the switch between protection and harm depends on concentration, cell type, pathological setting, and the specific lactylation site involved. Excessive lactate accumulation accompanies the acidic, hypoxic conditions of injury and chronic disease, where it can exacerbate oxidative damage and support inflammatory programs. In neurodegenerative diseases characterized by protein aggregation—amyloid-beta and tau in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, huntingtin in Huntington’s disease—altered post-translational modification landscapes may influence how proteins misfold, aggregate, and evade clearance. Lactylation of proteins involved in aggregation or in the machinery that clears misfolded proteins could tip the balance toward pathology. Similarly, in amyotrophic lateral sclerosis, where motor neuron degeneration is coupled to defects in the motor neuron lactate shuttle and disrupted energy metabolism, the direction of lactate flux may determine whether supporting cells nourish or starve the vulnerable neurons they surround.

The disease-specific evidence reviewed by the authors paints a picture of context-dependence rather than simple causation. In Alzheimer’s disease, impaired glucose metabolism and reduced lactate handling are observed alongside amyloid precursor protein pathology, and altered lactate dynamics in the cerebrospinal fluid reflect broader metabolic decline; yet lactate’s neurotrophic and anti-inflammatory actions suggest potential benefit if delivered appropriately. In Parkinson’s disease, dopaminergic neurons in the substantia nigra are energetically fragile, with high mitochondrial demand and susceptibility to reactive oxygen species, making metabolic support attractive but also raising the stakes of any intervention that perturbs redox balance. In Huntington’s disease, mutant huntingtin disrupts transcription and metabolism broadly, and lactylation-dependent gene regulation could either compensate for or compound these defects. The unifying insight is that lactate is not simply good or bad; it is a dose-, timing-, and site-dependent variable that must be read in the context of each disease stage and cellular environment.

Therapeutic implications follow directly from this framing, and the review evaluates several strategies for manipulating lactate metabolism and lactylation. Approaches include modulating lactate dehydrogenase activity, targeting monocarboxylate transporters to redirect lactate flux between cells, pharmacologically shifting metabolism with agents such as dichloroacetate that favor mitochondrial oxidation over glycolysis, and exploiting exercise—high-intensity interval training elevates circulating lactate and has been associated with enhanced neurotrophic signaling and adult hippocampal neurogenesis. Enzymes that write and erase lysine lactylation marks are also candidate drug targets, analogous to the histone acetyltransferases and deacetylases that have yielded epigenetic therapies in oncology. The challenge, as the authors stress, is achieving the right modification at the right site in the right cells: systemic manipulation of lactate would simultaneously affect neurons, astrocytes, microglia, endothelial cells, and peripheral immune cells, each of which may respond differently.

The review’s conclusion is a call for precision rather than enthusiasm. Lactate and protein lactylation exhibit a genuine regulatory duality in neurogenesis and neurodegenerative disease, and the factors that determine which face prevails—concentration, cell type, pathological context, and lactylation site—are only beginning to be mapped. Site-specific mapping of the lactylome in human disease tissue, tools for cell-type-selective manipulation of lactylation, and biomarkers that report on lactylation state in living patients are among the needs the authors identify for clinical translation. If those gaps close, the molecule once dismissed as metabolic exhaust may become a lever for regenerating the aging and diseased brain—one lysine residue at a time.

Subject of Research: Roles of lactate metabolism and lysine lactylation in adult neurogenesis and neurodegenerative disease

Article Title: Roles of lactate and protein lactylation in neurogenesis and neurodegenerative disease

Article References: Zhou, X., Han, J., Cui, X., Wu, S., Lu, Z., & Zong, S. (2026). Roles of lactate and protein lactylation in neurogenesis and neurodegenerative disease. Journal of Translational Medicine, 24(1), Article 1210. https://doi.org/10.1186/s12967-026-08940-2

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08940-2

Keywords: lactate, protein lactylation, neurogenesis, neural stem cells, epigenetics, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, astrocyte-neuron lactate shuttle, histone modification, neuroinflammation