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Review

Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review)

  • Authors:
    • Xunjie Jian
    • Chang Cheng
    • Wenjie Lu
    • Hui Peng
    • Diqi Yang
  • View Affiliations / Copyright

    Affiliations: School of Tropical Agriculture and Forestry, Hainan University, Hainan, Haikou 570228, P.R. China
  • Article Number: 11
    |
    Published online on: November 3, 2025
       https://doi.org/10.3892/ijmm.2025.5682
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Abstract

Histone lactylation, a novel epigenetic modification, has emerged as a critical mediator of various physiological and pathological processes. The present review elucidates the molecular mechanisms of lysine lactylation (Kla) and its influence on gene expression modulation. In addition, previous findings regarding the mechanisms of Kla and its impact on metabolic regulation, inflammation and tumorigenesis are summarized. Histone lactylation influences macrophage polarization, promotes tumor immune evasion, and affects osteoblast differentiation and embryonic development. While promising as a therapeutic target, research progress is currently hindered by methodological limitations in terms of lactylation quantification and manipulation. The current review not only summarizes fundamental insights into Kla‑mediated disease pathogenesis but also critically addresses existing knowledge gaps. By highlighting the dynamic interplay between lactylation and metabolic regulation, novel perspectives are provided on the biological importance of this posttranslational modification. Ultimately, the aim of this review is to identify innovative approaches for targeting lactylation‑mediated pathways in disease treatment.
View Figures

Figure 1

Graphical abstract: The lactate
produced by glycolysis is first converted into lactyl-CoA, which
contributes a lactyl group to the histone tail with the help of the
writer, and then read by the reader to regulate gene expression.
This lactate-dependent posttranslational modification on histones
is named histone lactylation. Histone lactylation occurs in a wide
range of physiological and pathological processes, such as
differentiation of osteocytes and cancer progress. Created with
BioRender.com.

Figure 2

Histone lactylation serves a crucial
role in a variety of physiological processes. (A) Histone
lactylation, driven by LDHA and lactate, activates key osteogenic
genes and promotes osteoblast differentiation, which is crucial for
skeletal development and can mitigate osteoporosis in BMSCs. (B)
Lactate serves as a key molecule in brain metabolism and signaling,
modulating neuronal activity and histone lactylation, which impacts
gene expression and glial cell function, with potential
implications for nervous system development and function. (C)
Histone lactylation is essential for early mammalian embryonic
development, influencing gene expression and epigenetic regulation,
and is affected by lactate and oxygen levels. Created with
BioRender.com. BMSCs, bone mesenchymal stem cells; EC, endothelial
cell; ESCs, embryonic stem cells; H3K18la, H3 lysine 18
lactylation; LDHA, lactate dehydrogenase A.

Figure 3

Histone lactylation serves a key role
in various pathological processes, including tumor progression,
fibrotic diseases, inflammatory responses and other conditions such
as neurodegenerative and cardiovascular diseases, highlighting its
potential as a therapeutic target. Created with BioRender.com. AD,
Alzheimer's disease; FTO, fat mass and obesity-associated protein;
HCC, hepatocellular carcinoma; HMGB1, high-mobility group box 1;
HSCs, hepatic stellate cells; Kla, lysine lactylation; METTL3,
methyltransferase-like 3; PKM2, pyruvate kinase 2; SASP,
senescence-associated secretory phenotype; TIMs, tumor-infiltrating
myeloid cells.
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Copy and paste a formatted citation
Spandidos Publications style
Jian X, Cheng C, Lu W, Peng H and Yang D: Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review). Int J Mol Med 57: 11, 2026.
APA
Jian, X., Cheng, C., Lu, W., Peng, H., & Yang, D. (2026). Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review). International Journal of Molecular Medicine, 57, 11. https://doi.org/10.3892/ijmm.2025.5682
MLA
Jian, X., Cheng, C., Lu, W., Peng, H., Yang, D."Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review)". International Journal of Molecular Medicine 57.1 (2026): 11.
Chicago
Jian, X., Cheng, C., Lu, W., Peng, H., Yang, D."Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 11. https://doi.org/10.3892/ijmm.2025.5682
Copy and paste a formatted citation
x
Spandidos Publications style
Jian X, Cheng C, Lu W, Peng H and Yang D: Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review). Int J Mol Med 57: 11, 2026.
APA
Jian, X., Cheng, C., Lu, W., Peng, H., & Yang, D. (2026). Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review). International Journal of Molecular Medicine, 57, 11. https://doi.org/10.3892/ijmm.2025.5682
MLA
Jian, X., Cheng, C., Lu, W., Peng, H., Yang, D."Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review)". International Journal of Molecular Medicine 57.1 (2026): 11.
Chicago
Jian, X., Cheng, C., Lu, W., Peng, H., Yang, D."Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 11. https://doi.org/10.3892/ijmm.2025.5682
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