Histone Lactylation as an Epigenetic Regulator in Alzheimer’s Disease Pathophysiology: A Narrative Review

Abstract Alzheimer’s disease (AD) represents a progressive neurodegenerative disorder clinically defined by insidious multidomain cognitive deterioration and neuropathologically characterized by extracellular amyloid-β plaques and intraneuronal neurofibrillary tangles. Its pathological core includes β-amyloid protein (Aβ) deposition, neurofibrillary tangles (NFT) and neuroinflammation, seriously threatening the health of the elderly population worldwide. With the intensification of population aging, the socio-economic burden brought by AD is increasingly heavy. However, its complex pathogenesis has not been fully clarified, and there is an urgent need to explore new molecular markers and therapeutic targets. Lactylation, a novel metabolite-derived post-translational modification (PTM) where lactate groups are covalently conjugated to lysine residues, has recently been implicated in the pathological process of AD. For example, lactylation at histone H4 lysine 12 (H4K12la) has been reported to promote neuroinflammation via a “glycolysis/H4K12la/PKM2” positive feedback loop and activate the NLRP3 inflammasome-mediated pyroptosis. Similarly, lactylation at histone H3 lysine 18 (H3K18la) may enhance microglial activation through the NF-κB pathway. However, the role of lactylation in AD appears to be complex and context-dependent, as evidenced by seemingly contradictory findings regarding its impact on Aβ pathology. Therefore, this article reviews the relevant literature on lactylation and AD, summarizes the possible mechanisms by which lactylation regulates AD, and provides theoretical basis and reference for the related research on molecular markers and therapeutic targets of AD.

• Publication year

  2025

• Venue

  Journal of Inflammation Research

• Publication date

  2025-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.2147/JIR.S557031PMID 41243988PMCID 12619604
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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