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Helicobacter pylori and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review)

  • Authors:
    • Youjia Liu
    • Fang Wang
    • Ya Deng
    • Yanxia Hu
    • Feihong Shu
    • Jie Yu
    • Guoyou Gou
    • Min Wen
    • Chen Luo
    • Xianmin Lu
    • Qian Du
    • Jingyu Xu
    • Rui Xie
  • View Affiliations / Copyright

    Affiliations: Department of Endoscopy and Digestive System, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China, Collaborative Innovation Center for Tissue Repair and Regenerative Medicine, Zunyi Medical University, Zunyi, Guizhou 563006, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 92
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    Published online on: February 9, 2026
       https://doi.org/10.3892/ijmm.2026.5763
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Abstract

Helicobacter pylori (H. pylori) is a Gram‑negative bacterial pathogen, and infection with this pathogen is a primary risk factor for gastric cancer (GC), often inducing chronic gastritis, which further increases the risk of cancer. Glycolysis carries out a key role in GC metabolism, serving as the primary energy pathway for cancer cells, particularly under hypoxic conditions. Enhanced glycolysis allows GC cells to sustain high proliferation rates and produce lactic acid, creating an acidic tumor microenvironment that promotes tumor progression. Understanding the mechanisms of H. pylori‑driven glycolysis may provide new insights into GC pathogenesis and reveal novel therapeutic targets. The present review addresses advances in glycolysis research in GC, summarizing its characteristics, identifying key mediators involved in metabolic reprogramming and exploring potential molecular mechanisms to recommend new targets for therapy.
View Figures

Figure 1

H. pylori-induced inflammatory
and oxidative pathways converge on glycolytic reprogramming to
drive GC progression. Pathogenic mechanisms of H. pylori
infection in GC. The virulence factor CagA activates JAK/STAT3,
NF-κB and PI3K/AKT/mTOR pathways, inducing pro-inflammatory
cytokines (IL-6, IL-8 and TNF-α) and promoting cell proliferation.
These signals upregulate glycolytic regulators (HIF-1α, GLUTs, HK2
and LDH-A), driving the Warburg effect with increased glucose
uptake and lactate production. Concurrently, H. pylori
stimulates ROS generation, leading to oxidative stress, DNA damage
and tumor microenvironment remodeling, including CAF activation,
angiogenesis and immune cell infiltration. Figure created using
Procreate: Savage Interactive Pty Ltd (Version 5.4.7) and Adobe
Illustrator (Adobe Inc 2025; Version 29.x). H. pylori,
Helicobacter pylori; GC, gastric cancer; CagA,
cytotoxin-associated gene A; HK2, Hexokinase 2; ROS, reactive
oxygen species; GLUTs, glucose transporters; HIF-1α,
hypoxia-inducible factor 1-α; LDH-A, lactate dehydrogenase A;
TNF-α, tumor necrosis factor α; CAF, cancer-associated
fibroblasts.

Figure 2

H. pylori infection under
hyperglycemic conditions. H. pylori infection releases CagA
and inflammatory cytokines (IL-8, IL-1β, IL-6 and TNF-α),
activating IGF-1R-mediated PI3K/AKT/mTOR and IR-A/STAT3 pathways.
Hyperinsulinemia elevates IGF-1/IGF-2 levels, further stimulating
these cascades. Together, these signals promote glycolysis,
proliferation, angiogenesis, invasion and chronic inflammation,
reinforcing the Warburg effect in GC cells. Figure created using
Procreate, Savage Interactive Pty Ltd (Version 5.4.7) and Adobe
Illustrator, Adobe Inc 2025 (Version 29.x). H. pylori,
Helicobacter pylori; CagA, Cytotoxin-associated gene A; GC,
gastric cancer; IGF-1/2, insulin-like growth factor-1/2; IR-A,
insulin receptor isoform A.

Figure 3

TME regulated by H. pylori
infection. (A) The polarization of macrophages into M1 and M2
phenotypes, which is influenced by hypoxia inducible factor-1 and
lactic acid. M1 macrophages produce pro-inflammatory cytokines,
including IL-6, IL-8 and TNF-α, which contribute to anti-tumor
immunity. By contrast, M2 macrophages secrete anti-inflammatory
cytokines such as IL-4, IL-10 and IL-13, promoting tumor growth and
immune evasion. (B) Glycolytic Pathway Alterations in H.
pylori-Associated GC Cells. CAFs positioned in the tumor
microenvironment secrete TGF-β, which activates Smad 2/3 signaling
in GC cells. This signaling enhances HK2-mediated glycolysis,
leading to increased production of glucose-6-phosphate, diversion
into the PPP for ribose-5-phosphate and nucleotide synthesis, and
conversion to lactate via LDH-A/B. Lactate is exported from CAFs or
cancer cells, acidifying the microenvironment and promoting EMT.
Meanwhile, pyruvate generated during glycolysis enters the TCA
cycle through PDH, producing acetyl-CoA, citrate, OAA and αKG. This
schematic illustrates the metabolic cross-talk between H.
pylori-associated GC cells and CAFs, highlighting how
stromal-derived signaling and metabolites reinforce tumor
glycolysis and biosynthetic activity within the 'reverse Warburg
effect' framework. Figure created using Procreate (Version 5.4.7);
Savage Interactive Pty Ltd and Adobe Illustrator, Adobe Inc 2025
(Version 29.x). H. pylori, Helicobacter pylori. GC,
gastric cancer; TNF-α, tumor necrosis factor α; TGF-β, transforming
growth factor-β; HK2, Hexokinase 2; Glucose 6-P,
Glucose-6-Phosphate; PPP, pentose phosphate pathway; PDH, pyruvate
dehydrogenase; EMT, epithelial-mesenchymal transition; LDH A/B,
lactate dehydrogenase A/B; OAA, oxaloacetate; αKG,
α-ketoglutarate.
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Spandidos Publications style
Liu Y, Wang F, Deng Y, Hu Y, Shu F, Yu J, Gou G, Wen M, Luo C, Lu X, Lu X, et al: <em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review). Int J Mol Med 57: 92, 2026.
APA
Liu, Y., Wang, F., Deng, Y., Hu, Y., Shu, F., Yu, J. ... Xie, R. (2026). <em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review). International Journal of Molecular Medicine, 57, 92. https://doi.org/10.3892/ijmm.2026.5763
MLA
Liu, Y., Wang, F., Deng, Y., Hu, Y., Shu, F., Yu, J., Gou, G., Wen, M., Luo, C., Lu, X., Du, Q., Xu, J., Xie, R."<em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review)". International Journal of Molecular Medicine 57.4 (2026): 92.
Chicago
Liu, Y., Wang, F., Deng, Y., Hu, Y., Shu, F., Yu, J., Gou, G., Wen, M., Luo, C., Lu, X., Du, Q., Xu, J., Xie, R."<em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review)". International Journal of Molecular Medicine 57, no. 4 (2026): 92. https://doi.org/10.3892/ijmm.2026.5763
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x
Spandidos Publications style
Liu Y, Wang F, Deng Y, Hu Y, Shu F, Yu J, Gou G, Wen M, Luo C, Lu X, Lu X, et al: <em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review). Int J Mol Med 57: 92, 2026.
APA
Liu, Y., Wang, F., Deng, Y., Hu, Y., Shu, F., Yu, J. ... Xie, R. (2026). <em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review). International Journal of Molecular Medicine, 57, 92. https://doi.org/10.3892/ijmm.2026.5763
MLA
Liu, Y., Wang, F., Deng, Y., Hu, Y., Shu, F., Yu, J., Gou, G., Wen, M., Luo, C., Lu, X., Du, Q., Xu, J., Xie, R."<em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review)". International Journal of Molecular Medicine 57.4 (2026): 92.
Chicago
Liu, Y., Wang, F., Deng, Y., Hu, Y., Shu, F., Yu, J., Gou, G., Wen, M., Luo, C., Lu, X., Du, Q., Xu, J., Xie, R."<em>Helicobacter pylori</em> and hyperglycemia fuel gastric cancer glycolysis: Mechanisms and targeted intervention (Review)". International Journal of Molecular Medicine 57, no. 4 (2026): 92. https://doi.org/10.3892/ijmm.2026.5763
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