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Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)

  • Authors:
    • Yang Liu
    • Yongfeng Li
    • Heng Ma
    • Shichang Deng
    • Chao Cheng
  • View Affiliations / Copyright

    Affiliations: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 73
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    Published online on: January 26, 2026
       https://doi.org/10.3892/ijmm.2026.5744
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Abstract

Pancreatic cancer has nearly doubled in incidence over the past two decades, becoming one of the deadliest types of malignancy in humans, with poor prognosis. With advances in modern medicine, the 5‑year survival rate for pancreatic cancer has increased from <5% in 1990 to ~10% in 2021. Most patients are diagnosed at an advanced stage, and ~20% of patients diagnosed at an early stage are eligible for surgical resection, with a 5‑year survival rate after surgery of up to 25%. With the aging population, the incidence of pancreatic cancer is expected to continue rising. The gut microbiota, a crucial ecosystem, comprises >1x1014 microorganisms that influence the development of pancreatic cancer through immune modulation and metabolites. Circadian rhythms, as a conserved molecular feedback loop, regulate cell metabolism and immune function, and their dysregulation is associated with metabolic disorders and tumor progression. Circadian rhythm disruption not only affects the gut microbiota and its metabolites but also accelerates pancreatic cancer progression through mechanisms such as promoting inflammation, immune suppression and drug resistance. The present review summarizes the impact of circadian rhythm dysregulation on the gut microbiota and its metabolites, specific microbiota associated with pancreatic cancer and their mechanisms in tumor progression and aims to deepen the understanding of the role of gut microbiota in pancreatic cancer treatment, providing a theoretical basis for future therapeutic strategies.

View Figures

Figure 1

Circadian rhythm and gut microbiota.
Disruption of the circadian rhythm not only leads to increased
metabolites such as catecholamines and glucocorticoids, which
trigger mast cell degranulation and damage the intestinal barrier,
but also induces alterations in the gut microbiota. This results in
the accumulation of harmful metabolites such as lipopolysaccharide,
which can translocate through the intestinal barrier into the
systemic circulation, leading to T cell exhaustion. Changes in gut
microbiota-induced metabolites modulate the expression of host
genes, such as Clock and Bmal1, further disrupting circadian
rhythms. Figure created using Adobe Illustrator 2025 (Adobe, Inc.).
Bmal1, brain and muscle ARNT-like 1; SCFA, short-chain fatty
acid.

Figure 2

Microbial infection and inflammatory
pathways in pancreatitis and cancer development. Dysbiosis of the
gut microbiota leads to the proliferation of harmful bacteria,
disrupting the intestinal epithelial barrier and allowing
pathogenic bacteria to migrate to the pancreas, triggering an
inflammatory response. NLRs activate the NF-κB signaling pathway
and promote inflammasome formation following recognition of MAMPs.
A key component of inflammasomes, caspase-1, facilitates the
maturation of pro-inflammatory cytokines such as IL-1β and IL-18,
exacerbating the inflammatory response. NOD1 responds to gut
microbiota and activates the NF-κB and STAT3 pathways, leading to
the production of MCP-1, which recruits CCR2+
inflammatory cells to the pancreas. Persistent activation of STAT3
promotes the production of cytokines and chemokines such as IL-6
and COX2. Figure created using Adobe Illustrator 2025 (Adobe,
Inc.). MAMP, microbial-associated molecular pattern; NLR, Nod-like
receptor; MCP, monocyte chemoattractant protein-1; CCR, C-C
chemokine receptor.

Figure 3

Gut microbiota and immune suppression
in pancreatic cancer. Alterations in the gut microbiota within
pancreatic cancer tissue lead to immune suppression in the tumor
microenvironment. These microbiota changes result in a decrease in
Th1 cells, an increase in Th17 cells, suppression of M1 macrophage
polarization and decreased PD-1 receptor expression on T cells. The
microbiota shift promotes the expression of TLR4 and TLR7 on cancer
cells. These microbial changes also contribute to reduced immune
cell infiltration and lower secretion of immune factors at the
tumor site, which facilitates tumor progression. Figure created
using Adobe Illustrator 2025 (Adobe, Inc.). Th, T helper; TLR,
toll-like receptor.

Figure 4

Gut microbiota metabolites and
pancreatic cancer progression. Lactic acid, a short-chain fatty
acid, is absorbed by CAFs via MCT1, promoting CAF proliferation and
upregulating IL-6 expression, which suppresses immune cell activity
and enhances CAF formation via α-ketoglutarate-dependent TET
enzymes. Butyrate increases alkaline phosphatase activity,
facilitating the conversion of CD18 to CD11 cells. Additionally,
butyrate inhibits the cell cycle progression, increases the
expression of pro-apoptotic proteins Bax and caspase-7 and
suppresses pancreatic cancer cell proliferation. Butyrate enhances
immune cell activity and stimulates the production of immune
factors such as CD25, IFN-γ and TNF-α. LPS, via the
TLR4/MyD88/NF-κB signaling pathway, elevates the production of
PD-L1 and TGF-β1 in tumor cells, promoting pancreatic cancer
progression. LPS promotes M1 polarization of macrophages,
contributing to pancreatic inflammation. Polyamines drive tumor
proliferation by promoting the synthesis of purine and pyrimidine
nucleotides. Figure created using Adobe Illustrator 2025 (Adobe,
Inc.). CAF, cancer-associated fibroblast; MCT, monocarboxylate
transporter; TET, 10-11 translocation; LPS, lipopolysaccharide;
TLR, toll-like receptor.
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Copy and paste a formatted citation
Spandidos Publications style
Liu Y, Li Y, Ma H, Deng S and Cheng C: <p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>. Int J Mol Med 57: 73, 2026.
APA
Liu, Y., Li, Y., Ma, H., Deng, S., & Cheng, C. (2026). <p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>. International Journal of Molecular Medicine, 57, 73. https://doi.org/10.3892/ijmm.2026.5744
MLA
Liu, Y., Li, Y., Ma, H., Deng, S., Cheng, C."<p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 73.
Chicago
Liu, Y., Li, Y., Ma, H., Deng, S., Cheng, C."<p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 73. https://doi.org/10.3892/ijmm.2026.5744
Copy and paste a formatted citation
x
Spandidos Publications style
Liu Y, Li Y, Ma H, Deng S and Cheng C: <p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>. Int J Mol Med 57: 73, 2026.
APA
Liu, Y., Li, Y., Ma, H., Deng, S., & Cheng, C. (2026). <p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>. International Journal of Molecular Medicine, 57, 73. https://doi.org/10.3892/ijmm.2026.5744
MLA
Liu, Y., Li, Y., Ma, H., Deng, S., Cheng, C."<p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 73.
Chicago
Liu, Y., Li, Y., Ma, H., Deng, S., Cheng, C."<p>Mechanistic insights into pancreatic cancer progression from circadian rhythm disruption and gut microbiota dysbiosis (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 73. https://doi.org/10.3892/ijmm.2026.5744
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