Histone Lactylation Emerges as Key Epigenetic Link Between Glycolysis and Ferroptosis in Neurological Diseases
Key Insights
Histone lactylation, a novel epigenetic modification linking glycolytic lactate to chromatin, forms a "glycolysis-lactylation-ferroptosis (search)" regulatory axis implicated in Alzheimer's, Parkinson's, stroke, and ALS.
In Alzheimer's disease (search), H4K12 lactylation drives a positive feedback loop with PKM2 (search) in microglia adjacent to Aβ plaques, sustaining neuroinflammation and microglial dysfunction.
Lactylation modifications at H3K18 and H3K9 sites directly regulate ferroptosis (search)-related genes including ACSL4 (search), TFRC (search), and GPX4 (search), creating a dual regulatory mode that both promotes and inhibits ferroptosis.
A growing body of research has positioned histone lactylation—a recently discovered epigenetic modification that covalently attaches lactate to histone lysine residues—as a central mechanistic bridge connecting cellular metabolic reprogramming to ferroptosis (search) in neurological diseases. First identified by Zhang et al. in 2019, this modification establishes a direct link between glycolytic flux and gene transcription, forming what researchers now describe as a "glycolysis-lactylation-ferroptosis" regulatory axis with profound implications for Alzheimer's disease (search) (AD), Parkinson's disease (search) (PD), ischemic stroke (search), and amyotrophic lateral sclerosis (search) (ALS).
The chemical basis of histone lactylation involves the conversion of lactate to lactyl-CoA, which is then transferred to specific lysine sites—predominantly H3K9, H3K18, and H3K56—by histone acetyltransferases such as p300/CBP (search). The "eraser" function is carried out by histone deacetylases (HDAC1-3) and NAD+-dependent sirtuins (SIRT1-3), creating a dynamic regulatory system that translates metabolic state into epigenetic signals at the chromatin level.
Metabolic Reprogramming Drives Lactylation in the Diseased Brain
In neurological diseases, activated microglia and astrocytes undergo significant metabolic reprogramming, shifting from oxidative phosphorylation to glycolysis. This shift, while enabling rapid ATP generation, produces substantial lactate accumulation that serves as both a signaling molecule and a substrate for histone lactylation.
"In AD, H4K12-la levels are elevated in microglia adjacent to Aβ plaques. This lactate-dependent histone modification enriches at the promoter regions of glycolytic genes and activates their transcription, forming a glycolysis/H4K12-la/PKM2 (search) positive feedback loop that exacerbates microglial dysfunction," according to research published in Frontiers in Molecular Neuroscience. This loop has been confirmed in brain samples from both AD patients and 5XFAD mice.
Similarly, in cerebral ischemia-reperfusion injury (CIRI), a high-glycolysis subpopulation appears in microvascular endothelial cells, characterized by mitochondrial dysfunction and necroptosis activation—a process associated with lactate accumulation and increased histone lactylation. After spinal cord injury, the key glycolytic regulator PFKFB3 in astrocytes is significantly upregulated, and its absence exacerbates neuronal ferroptosis (search) and hinders functional recovery.
Dual Regulation of Ferroptosis (search) by Lactylation
Histone lactylation exerts a "dual regulatory" mode on the ferroptosis (search) pathway. On one hand, it promotes ferroptosis by activating pro-ferroptosis genes. H3K18-la modification has been shown to specifically enrich in the promoter regions of ACSL4 (search), directly driving its transcriptional activation. In a CIRI model, lactate-induced histone H4K12-la in neurons was enriched in the promoter region of the iron transporter-encoding gene Zip14, promoting chromatin accessibility and triggering neuronal ferroptosis.
On the other hand, lactylation can inhibit anti-ferroptosis (search) gene expression. Elevated lactate levels lead to decreased SIRT3 (search) expression, further promoting ACSL4 (search) lactylation modification and ferroptosis activation. This dual mechanism makes cells more susceptible to ferroptosis in pathological environments with hyperactive glycolysis.
Disease-Specific Insights
In PD, dopaminergic neurons in the substantia nigra pars compacta exhibit selective vulnerability due to their high basal metabolic rate, pacemaking activity, and inherent oxidative stress environment. Environmental neurotoxins MPTP and rotenone can inhibit pyruvate dehydrogenase complex activity, increase lactate production, and drive histone lactylation in the promoter region of the DDIT4 gene, promoting dopaminergic neuron death.
In ALS, activated astrocytes and microglia exhibit hyperactive glycolysis that may drive transformation into a neurotoxic phenotype. Research indicates that in ALS cell models carrying FUS mutations, cells exhibit increased susceptibility to ferroptosis (search), manifested as exacerbated lipid peroxidation and an imbalanced antioxidant system.
For ischemic stroke (search), the "lactate storm" following reperfusion drives pathological hyperlactylation that significantly upregulates neuronal susceptibility to ferroptosis (search) in the penumbra, leading to delayed neuronal death and infarct expansion. Magnetic resonance spectroscopy imaging has confirmed that lactate signals are significantly elevated in the infarct core and surrounding areas in acute ischemic stroke patients.
Therapeutic Opportunities and Challenges
Targeting key nodes of this axis has shown therapeutic promise. Inhibiting key glycolytic enzymes such as PKM2 (search), using p300 inhibitors like C646, or activating delactylases through SIRT activators have demonstrated neuroprotective effects in animal models. Electroacupuncture treatment can effectively reduce H4K12-la levels in neurons by inhibiting PKM2, while genetically silencing LDHA (search) can reduce lactate production and lower overall histone lactylation levels.
However, significant challenges remain for clinical translation. Precisely distinguishing between physiological and pathological lactylation modifications is crucial, as lactate mediates lactylation involved in normal brain functions including memory formation and neuronal excitability regulation. Blood-brain barrier permeability poses a major obstacle in drug development, and engineered nano-drug delivery systems—particularly exosome-based platforms—are being explored to overcome this limitation.
The identification of histone lactylation-related genes as potential biomarkers also shows promise. In AD, bioinformatic analysis identified ARID5B, SESN1, and XPA as key genes with diagnostic potential. In spinal cord injury studies, eight histone lactylation modification-related genes including HDAC2, GCN5, and LDHA (search) were identified as important biomarkers, with their diagnostic value confirmed through receiver operating characteristic curve analysis.