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Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review)

  • Authors:
    • Xinyi Liang
    • Tianlin Wang
    • Jiale Ma
    • Shuangmei Zhao
    • Wang Gao
    • Yan Yang
    • Xinyuan Zhang
    • Huizhen Li
  • View Affiliations / Copyright

    Affiliations: Department of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300250, P.R. China
    Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 86
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    Published online on: June 3, 2026
       https://doi.org/10.3892/ijo.2026.5899
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Abstract

Gastric cancer (GC), which primarily originates from gastric mucosal epithelium, is driven by factors such as Helicobacter pylori infection, genetic susceptibility and lifestyle. GC poses a serious threat to patient survival and quality of life. Metabolic reprogramming, a hallmark of tumorigenesis and progression, enables cancer cells to continuously adapt their energy metabolism to support proliferation, invasion, metastasis and drug resistance. Circular RNAs (circRNAs) are a class of non‑coding RNAs characterized by a covalently closed circular structure, which confers high stability. They are differentially expressed in tumor cells and facilitate tumor proliferation and metastasis through multiple mechanisms such as microRNA sponging, protein binding, short peptide translation and N6‑methyladenosine modification. Furthermore, circRNAs contribute to tumor metabolic remodeling, meeting the energy demands of tumor cells by regulating key enzymes and transporters involved in metabolic pathways, thereby modulating the synthesis or degradation of metabolites. The present review summarizes the mechanisms by which circRNAs mediate different metabolic modes during the initiation and progression of GC as well as discusses their potential as biomarkers for GC. By systematically elucidating the intricate interactions between circRNAs and metabolic reprogramming in GC, the present study aims to provide a theoretical foundation for the development of innovative therapeutic strategies against GC.
View Figures

Figure 1

Schematic illustration of circRNA
biogenesis and functions in the nucleus and cytoplasm. (A)
Canonical linear splicing of precursor mRNA produces a linear
transcript containing a 5' cap and 3' poly(A) tail, whereas
back-splicing generates circRNA molecules. (B) EIciRNAs: Formed
when back-splicing retains an intron between the circularizing
exons, mediated by QKI and facilitated by base-pairing
interactions. (C) EcircRNAs: Formed by back-splicing of exons (such
as Exon2 and Exon3) with the introns removed. This results in a
circular molecule composed entirely of exons. (D) ciRNAs: Generated
from introns that escape debranching and form a circle (shown here
as Exon1-derived ciRNA). The diagram also illustrates an EIciRNA
variant comprising Exon1 directly spliced to Exon3/4. circRNAs (E)
acting as miRNA sponges, (F) interacting with RBPs, (G) serving as
templates for cap-independent translation via IRESs and (H)
undergoing m6A-dependent translation mediated by
Mettl3/14 and eIF4G2. circRNA, circular RNA; EIcircRNAs,
exon-intron circRNAs; EcircRNAs, exonic circRNAs; ciRNAs, intronic
circRNAs; RBPs, RNA-binding proteins; IRESs, internal ribosome
entry sites; m6A, N6-methyladenosine; Mettl,
methyltransferase-like; QKI, quaking; FTO, complex and fat mass and
obesity-associated protein. Created in Adobe Illustrator.

Figure 2

Overview of the metabolic pathways
linking glycolysis, lipid metabolism, amino acid metabolism and
nucleotide metabolism. (A) Glucose uptake via GLUT1 triggers
glycolysis, producing pyruvate and lactate through the sequential
actions of HK2, PFK2, PKM2 and LDHA. Under anaerobic conditions,
lactate is exported and can re-enter cells via MCTs, serving as a
substrate for lactyl-CoA formation that drives histone lactylation.
(B) FAs imported through CD36 and FABP undergo activation to
acyl-CoA, conversion to malonyl-CoA and oxidation via mitochondrial
CPT1/2, producing ATP, NADH and FADH2 through the TCA
cycle. Lipid droplets act as energy reservoirs during starvation.
(C) Amino acids, including BCAAs and glutamine transported by LAT
and SLC1A5, feed into the TCA cycle to replenish intermediates such
as α-KG. (D) Parallel to glycolysis, the PPP generates NADPH and
ribose intermediates to support nucleotide synthesis and one-carbon
metabolism. Together, these integrated metabolic routes coordinate
carbon flux and epigenetic regulation through lactate-derived
histone modifications. HK2, hexokinase 2; PFK2,
phosphofructokinase-2; PKM2, pyruvate kinase M2; MCTs,
monocarboxylate transporters; FA, fatty acid; CPT, carnitine
palmitoyltransferase; TCA, tricarboxylic acid; PPP, pentose
phosphate pathway; LAT, L-type amino acid transporter; SLC1A5,
solute carrier family 1 member 5; α-KG, α-ketoglutarate; GLUT1,
glucose transporter 1; LDHA, lactate dehydrogenase A; FABP, fatty
acid-binding protein; BCAAs, branched-chain amino acids; G-6-P,
glucose-6-phosphate; F-6-P, fructose-6-phosphate; FDP,
fructose-1,6-bisphosphate; PEP, phosphoenolpyruvate; Glu,
glutamate; Gln, glutamine. Created in Adobe Illustrator.

Figure 3

Workflow for the detection and
analysis of circRNAs in the body fluids of patients with gastric
cancer. Schematic overview illustrating sample sources and
analytical procedures for circRNA profiling. Plasma, serum,
serum-derived exosomes and gastric juice are collected from
patients and subjected to total RNA extraction. Extracted RNA is
subsequently analyzed by ddPCR or RT-qPCR for quantification and by
RNA sequencing for transcriptomic profiling. circRNA, circular RNA;
ddPCR, droplet digital PCR; RT-qPCR, reverse
transcription-quantitative PCR. Created in Adobe Illustrator.
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Copy and paste a formatted citation
Spandidos Publications style
Liang X, Wang T, Ma J, Zhao S, Gao W, Yang Y, Zhang X and Li H: Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review). Int J Oncol 69: 86, 2026.
APA
Liang, X., Wang, T., Ma, J., Zhao, S., Gao, W., Yang, Y. ... Li, H. (2026). Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review). International Journal of Oncology, 69, 86. https://doi.org/10.3892/ijo.2026.5899
MLA
Liang, X., Wang, T., Ma, J., Zhao, S., Gao, W., Yang, Y., Zhang, X., Li, H."Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review)". International Journal of Oncology 69.1 (2026): 86.
Chicago
Liang, X., Wang, T., Ma, J., Zhao, S., Gao, W., Yang, Y., Zhang, X., Li, H."Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review)". International Journal of Oncology 69, no. 1 (2026): 86. https://doi.org/10.3892/ijo.2026.5899
Copy and paste a formatted citation
x
Spandidos Publications style
Liang X, Wang T, Ma J, Zhao S, Gao W, Yang Y, Zhang X and Li H: Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review). Int J Oncol 69: 86, 2026.
APA
Liang, X., Wang, T., Ma, J., Zhao, S., Gao, W., Yang, Y. ... Li, H. (2026). Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review). International Journal of Oncology, 69, 86. https://doi.org/10.3892/ijo.2026.5899
MLA
Liang, X., Wang, T., Ma, J., Zhao, S., Gao, W., Yang, Y., Zhang, X., Li, H."Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review)". International Journal of Oncology 69.1 (2026): 86.
Chicago
Liang, X., Wang, T., Ma, J., Zhao, S., Gao, W., Yang, Y., Zhang, X., Li, H."Metabolic remodeling by circular RNAs in gastric tumorigenesis: From mechanisms to biomarker discovery (Review)". International Journal of Oncology 69, no. 1 (2026): 86. https://doi.org/10.3892/ijo.2026.5899
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