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Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review)

  • Authors:
    • Luna Zhang
    • Qianqian Li
    • Yuxin Deng
    • Yuanxia Zou
    • Li Wang
    • Jianchun Li
  • View Affiliations / Copyright

    Affiliations: Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 290
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    Published online on: August 18, 2025
       https://doi.org/10.3892/mmr.2025.13655
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Abstract

Tissue fibrosis represents a pathological condition characterized by excessive accumulation of extracellular matrix (ECM) components. Although historically considered a byproduct of glycolysis, lactate has emerged as a key signaling molecule influencing diverse physiological and pathological processes, including fibrosis. Roles have emerged for lactate metabolism and lactylation, a novel post‑translational modification, in regulating fibroblast activation, ECM deposition and fibrotic progression. The present review provides a comprehensive analysis of the current understanding of glycolysis, lactate and lactylation in tissue fibrosis, with emphasis on cardiac, liver, renal and pulmonary fibrosis. The present review examines how enhanced glycolysis supports the energetic and biosynthetic requirements of activated fibroblasts, how lactate functions as a signaling molecule promoting fibrogenesis and how lactylation connects metabolic changes to epigenetic regulation of gene expression. Furthermore, the present review explores potential therapeutic approaches targeting metabolic pathways and lactylation to mitigate fibrosis, while highlighting future directions in this rapidly evolving field.
View Figures

Figure 1

Diagram of lactate metabolism in the
cytoplasm. This chart illustrates the glucose metabolism pathways
within cells, including uptake, glycolysis, mitochondrial oxidation
and gluconeogenesis, reflecting the metabolic equilibrium. Under
aerobic conditions, glycolysis produces pyruvate and lactate.
Lactate can be oxidized through monocarboxylate transporters or
used in the gluconeogenesis process, and it also plays a role in
metabolic regulation. ATP, adenosine triphosphate; F-1,6-BP,
fructose-1,6-bisphosphate; fructose-6-p, fructose-6-phosphate;
GLUT, glucose transporter; glucose-6-p, glucose-6-phosphate;
glyceraldehyde-3-p, glyceraldehyde-3-phosphate; HK2, hexokinase 2;
IMM, inner mitochondrial membrane; LDH, lactate dehydrogenase; MCT,
monocarboxylate transporter; mLOC, mitochondrial lactate oxidation
complex; MPC, mitochondrial pyruvate carrier; NAD+,
nicotinamide adenine dinucleotide; OMM, outer mitochondrial
membrane; PDH, pyruvate dehydrogenase; PFKFB,
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFK1,
phosphofructokinase 1; PKM2, pyruvate kinase isoform M2; TCA,
tricarboxylic acid cycle.

Figure 2

Lactate-induced histone and
non-histone lactylation: Forms and dynamics. Lactylation of
histones and non-histone proteins is dynamically regulated by
writers (adding lactyl groups), erasers (removing lactyl groups)
and readers (recognizing modifications), influencing protein
function and signaling pathways.

Figure 3

Role of glycolysis-regulated
lactylation in tissue fibrosis. This schematic illustrates how the
glycolysis-lactylation metabolic axis drives fibrotic processes in
heart, liver, kidney and lungs through lactate transport and
histone lactylation mechanisms, elucidating the crucial role of
metabolic reprogramming in multi-organ fibrosis. MCT,
monocarboxylate transporter; EndoMT, endothelial-to-mesenchymal
transition; HK2, hexokinase 2; HSCs, hepatic stellate cells;
MyoFib, myofibroblast; TECs, tubular epithelial cells; AECs,
alveolar epithelial cells; PFKFB3,
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; ECM,
extracellular matrix.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang L, Li Q, Deng Y, Zou Y, Wang L and Li J: Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review). Mol Med Rep 32: 290, 2025.
APA
Zhang, L., Li, Q., Deng, Y., Zou, Y., Wang, L., & Li, J. (2025). Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review). Molecular Medicine Reports, 32, 290. https://doi.org/10.3892/mmr.2025.13655
MLA
Zhang, L., Li, Q., Deng, Y., Zou, Y., Wang, L., Li, J."Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review)". Molecular Medicine Reports 32.5 (2025): 290.
Chicago
Zhang, L., Li, Q., Deng, Y., Zou, Y., Wang, L., Li, J."Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review)". Molecular Medicine Reports 32, no. 5 (2025): 290. https://doi.org/10.3892/mmr.2025.13655
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang L, Li Q, Deng Y, Zou Y, Wang L and Li J: Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review). Mol Med Rep 32: 290, 2025.
APA
Zhang, L., Li, Q., Deng, Y., Zou, Y., Wang, L., & Li, J. (2025). Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review). Molecular Medicine Reports, 32, 290. https://doi.org/10.3892/mmr.2025.13655
MLA
Zhang, L., Li, Q., Deng, Y., Zou, Y., Wang, L., Li, J."Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review)". Molecular Medicine Reports 32.5 (2025): 290.
Chicago
Zhang, L., Li, Q., Deng, Y., Zou, Y., Wang, L., Li, J."Glycolysis to lactylation: Unraveling the metabolic and epigenetic landscape in tissue fibrosis (Review)". Molecular Medicine Reports 32, no. 5 (2025): 290. https://doi.org/10.3892/mmr.2025.13655
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