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Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review)

  • Authors:
    • Yuanbo Xu
    • Weili Wang
    • Yating Zhang
    • Yinqiu Fan
    • Wanying Dong
    • Jun Yang
  • View Affiliations / Copyright

    Affiliations: Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230031, P.R. China, Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui 230001, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 133
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    Published online on: May 20, 2026
       https://doi.org/10.3892/or.2026.9138
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Abstract

Gastric cancer (GC) is among the most prevalent malignant tumors worldwide, and its occurrence and progression are closely associated with metabolic abnormalities and remodeling of the tumor microenvironment. As an emerging metabolism‑related post‑translational modification, lactylation acts as a central hub connecting metabolic reprogramming and epigenetic regulation in tumor cells. The present review systematically describes the reprogramming features of lactate metabolism in the GC microenvironment; dissects the enzymatic system and molecular characteristics of lactylation; and reveals a bidirectional positive feedback loop in which histone H3 lysine 18 lactylation (H3K18la) promotes lactate production by upregulating glycolytic genes, and lactate accumulation, in turn, enhances H3K18la levels. A three‑dimensional regulatory network of ‘metabolic reprogramming‑epigenetic regulation‑immune microenvironment remodeling’ is thereby established in GC. The present review also reveals the clinical value of lactylation as a prognostic biomarker for GC, proposes combination therapeutic strategies targeting lactylation, and provides a theoretical basis and translational direction for the precise diagnosis and treatment of GC.
View Figures

Figure 1

Glycolytic pathway-mediated lactate
production and acidic tumor microenvironment formation in gastric
cancer cells. GLUT1, glucose transporter 1; HK2, hexokinase 2; G6P,
glucose-6-phosphate; PKM2, pyruvate kinase M2; LDHA, lactate
dehydrogenase A; MCT1, monocarboxylate transporter 1; MCT4,
monocarboxylate transporter 4; HIF-1α, hypoxia-inducible factor 1
α; c-Myc, cellular myelocytomatosis oncogene; NADH, nicotinamide
adenine dinucleotide (reduced form); NAD+, nicotinamide adenine
dinucleotide (oxidized form); OXPHOS, oxidative
phosphorylation.

Figure 2

Glutamine metabolism reprogramming
mediates lactate accumulation in gastric cancer cells. GLUT1,
glucose transporter 1; GIn, glutamine; Glu, glutamate; ASCT2,
alanine-serine-cysteine transporter 2; GLS, glutaminase; TCA,
tricarboxylic acid cycle; LDH, lactate dehydrogenase; ATF4,
activating transcription factor 4.

Figure 3

Lipid metabolic reprogramming in
gastric cancer cells. PI3K, phosphoinositide 3-kinase; AKT, protein
kinase B; mTORC1, mammalian target of rapamycin complex 1; SREBP-1,
sterol regulatory element-binding protein 1; CPT1A, carnitine
palmitoyltransferase 1A; TCA, tricarboxylic acid cycle; ATP,
adenosine triphosphate; Acetyl-CoA, acetyl coenzyme A; ACLY, ATP
citrate lyase; ACSS2, acyl-CoA synthetase short-chain family member
2; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1,
stearoyl-CoA desaturase 1.

Figure 4

Enzyme-dependent and non-enzymatic
spontaneous regulatory mechanisms of lactylation modification.
Lactyl-CoA, lactyl-coenzyme A; p300, E1A-associated protein p300;
HBO1, histone acetyltransferase binding to ORC1; AARS1, alanyl-tRNA
synthetase 1; La, lactylation; HDAC1-3, histone deacetylase 1–3;
SIRT1/2, sirtuin 1/2; MGO, methylglyoxal; GSH, glutathione; GLO1,
glyoxalase 1; GLO2, glyoxalase 2; LGSH, S-D-lactoylglutathione.

Figure 5

Lactylation modification regulates
the functional network of metabolic and immune microenvironment
remodeling in gastric cancer. GC, gastric cancer; HK2, hexokinase
2; la, lactylation (lysine lactylation, Kla); LDHA, lactate
dehydrogenase A; PKM2, pyruvate kinase M2; VDAC1, voltage-dependent
anion channel 1; AARS1, alanyl-tRNA synthetase 1; YAP,
Yes-associated protein; TEAD, TEA domain transcription factor;
c-Myc, cellular myelocytomatosis oncogene; p-H3, phosphorylated
histone H3; NSUN2, NOP2/Sun RNA methyltransferase 2; GCLC,
glutamate-cysteine ligase catalytic subunit; m5C, 5-methylcytosine;
METTL16, methyltransferase-like 16; SIRT2, sirtuin 2; CAF,
cancer-associated fibroblast; lncRNA, long non-coding RNA; H3K18la,
histone H3 lysine 18 lactylation; SIRT1, sirtuin 1; VCAM1, vascular
cell adhesion molecule 1; AKT, protein kinase B; mTOR, mammalian
target of rapamycin; CXCL1, C-X-C motif chemokine ligand 1;
GC-MSCs, gastric cancer mesenchymal stem cells; ASPM, abnormal
spindle-like microcephaly-associated protein; NCAPG, non-SMC
condensin I complex subunit G; BUB3, budding uninhibited by
benzimidazoles 3.
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Copy and paste a formatted citation
Spandidos Publications style
Xu Y, Wang W, Zhang Y, Fan Y, Dong W and Yang J: Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review). Oncol Rep 56: 133, 2026.
APA
Xu, Y., Wang, W., Zhang, Y., Fan, Y., Dong, W., & Yang, J. (2026). Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review). Oncology Reports, 56, 133. https://doi.org/10.3892/or.2026.9138
MLA
Xu, Y., Wang, W., Zhang, Y., Fan, Y., Dong, W., Yang, J."Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review)". Oncology Reports 56.1 (2026): 133.
Chicago
Xu, Y., Wang, W., Zhang, Y., Fan, Y., Dong, W., Yang, J."Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review)". Oncology Reports 56, no. 1 (2026): 133. https://doi.org/10.3892/or.2026.9138
Copy and paste a formatted citation
x
Spandidos Publications style
Xu Y, Wang W, Zhang Y, Fan Y, Dong W and Yang J: Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review). Oncol Rep 56: 133, 2026.
APA
Xu, Y., Wang, W., Zhang, Y., Fan, Y., Dong, W., & Yang, J. (2026). Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review). Oncology Reports, 56, 133. https://doi.org/10.3892/or.2026.9138
MLA
Xu, Y., Wang, W., Zhang, Y., Fan, Y., Dong, W., Yang, J."Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review)". Oncology Reports 56.1 (2026): 133.
Chicago
Xu, Y., Wang, W., Zhang, Y., Fan, Y., Dong, W., Yang, J."Dual roles of lactylation modification in gastric cancer: Crosstalk between metabolic reprogramming and epigenetic regulation (Review)". Oncology Reports 56, no. 1 (2026): 133. https://doi.org/10.3892/or.2026.9138
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