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Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review)

  • Authors:
    • Dan Pan
    • Yiwen Bao
    • Xiaoping Lu
    • Qiqun Gu
    • Yongchao Zhang
    • Yi Zheng
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, Guizhou 563000, P.R. China, Key Laboratory of Microbio and Infectious Disease Prevention and Control in Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550000, P.R. China, Department of Immunology, Center of lmmunomolecular Engineering, Innovation and Practice Base for Graduate Students Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China, Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China, Department of Gastroenterology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, Guizhou 563000, P.R. China
  • Article Number: 214
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    Published online on: September 30, 2025
       https://doi.org/10.3892/ijmm.2025.5655
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Abstract

Hepatocellular carcinoma (HCC) is among the most common and lethal cancers worldwide and is characterized by complex metabolic and immunological processes throughout its progression. Emerging research has underscored the critical involvement of the gut microbiota and its metabolites, particularly short‑chain fatty acids (SCFAs), in regulating the hepatic immune microenvironment and contributing to the development of HCC. SCFAs play essential roles in the gut‑liver axis by supporting immune homeostasis, modulating lipid metabolism and influencing immune escape mechanisms within the liver. SCFAs are not only products of gut microbiota metabolism but also key regulators of liver metabolism and immune responses. SCFAs play both positive and negative roles in HCC. SCFAs influence T‑cell function and immune responses through the activation of G‑protein‑coupled receptors and the inhibition of histone deacetylases. The present review provided an overview of the current knowledge concerning the regulatory dual effects of SCFAs on the immune microenvironment of HCC, examines their interactions with immune cells via the gut‑liver axis and evaluated their potential as adjuncts in HCC immunotherapy, with the goal of informing future therapeutic strategies.
View Figures

Figure 1

SCFAs and the gut-liver axis. Upon
entering the intestinal tract, dietary carbohydrates are
metabolized by the gut microbiota into SCFAs. Among them, butyrate
is absorbed by intestinal epithelial cells via transporters such as
MCT, SMCT and SLC26A. It helps maintain intestinal barrier
integrity by enhancing tight junctions and activating mucosal
immune responses. Other SCFAs enter the liver via the gut-liver
axis and portal vein, where they activate GPCRs and downstream
signaling pathways, including those involving PLC, PLA2, MAPK and
NF-κB, thereby promoting HCC development (42). In addition, acetate and propionate
can enter the nucleus and inhibit HDACs, leading to reduced
transcription of oncogenic genes and suppression of HCC progression
(43). By Figdraw. MAMP,
microbe-associated molecular pattern; MCT, monocarboxylate
transporter; SMCT, sodium-dependent multivitamin carrier
transporter; SL22A3, solute carrier family 22 member 3; TJ, tight
junction; GPR43, G-protein-coupled receptor 43; GPR41,
G-protein-coupled receptor 41; GPR109A, G-protein-coupled receptor
109A; PLC, phospholipase C; PLA2, phospholipase A2; IP3, inositol
1,4,5-trisphosphate; DAG, diacylglycerol; Ca2+, calcium Ion; CaMK,
calmodulin-dependent protein kinase; PKC, protein kinase C; HDAC,
histone deacetylase; AC, adenylyl cyclase; MAPK, mitogen-activated
protein kinase; COX, cyclooxygenase; c-FOS/JUN, proto-oncogene
transcription factors; BCL, B-cell lymphoma; NF-κB, nuclear factor
kappa-light-chain-enhancer of activated B cells; ICAM-1,
intercellular adhesion molecule 1; HCC, hepatocellular carcinoma;
CAZyme, carbohydrate active enzyme.

Figure 2

Dual roles of SCFAs in the HCC immune
microenvironment. The immune microenvironment of HCC is regulated
by a complex network of immune cells and molecular mechanisms.
SCFAs exert both promotive and suppressive effects within this
context. These two effects primarily depend on the balance of the
gut microbiota and dietary structure. When the balance is
disrupted, the effect of SCFAs on HCC shifts from positive to
negative (23,109,110). This illustration highlights the
critical roles of CD8+ T cells, CAR-T cells and CTLs in
antitumor immunity, along with the importance of cytokines such as
IFN-γ and TNF-α in driving immune responses. SCFAs influence immune
cell function by modulating metabolic and epigenetic regulators
such as HDACs. Conversely, immunosuppressive factors such as Tregs
and IL-10 inhibit immune activation and facilitate tumor immune
escape. Overall, SCFAs dynamically balance immune activation and
suppression in the HCC microenvironment by modulating metabolic and
inflammatory signaling pathways. By Figdraw. SCFAs, short-chain
fatty acids; HCC, hepatocellular carcinoma; Th1, T-helper 1; Th17,
T-helper 17; Treg, regulatory T Cells; TNF-α, tumor necrosis
factor-alpha; IFN-γ, interferon gamma; CD8+, cytotoxic T
Cells; CAR-T, chimeric antigen receptor T-cell; HDAC, histone
deacetylase; mTOR, mechanistic target of rapamycin; CTL, cytotoxic
T lymphocytes; FA, fatty acids; M1, classically activated
macrophages; PD-L1, programmed death-ligand 1; c-Myc,
proto-oncogene c-Myc; Suppresser Ig A+B, suppressor immunoglobulin
A and B; IL-10, interleukin 10; IL-17, interleukin 17; IL-22,
interleukin 22; γδ T, gamma delta T cells.
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Copy and paste a formatted citation
Spandidos Publications style
Pan D, Bao Y, Lu X, Gu Q, Zhang Y and Zheng Y: Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review). Int J Mol Med 56: 214, 2025.
APA
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., & Zheng, Y. (2025). Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review). International Journal of Molecular Medicine, 56, 214. https://doi.org/10.3892/ijmm.2025.5655
MLA
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., Zheng, Y."Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review)". International Journal of Molecular Medicine 56.6 (2025): 214.
Chicago
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., Zheng, Y."Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 214. https://doi.org/10.3892/ijmm.2025.5655
Copy and paste a formatted citation
x
Spandidos Publications style
Pan D, Bao Y, Lu X, Gu Q, Zhang Y and Zheng Y: Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review). Int J Mol Med 56: 214, 2025.
APA
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., & Zheng, Y. (2025). Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review). International Journal of Molecular Medicine, 56, 214. https://doi.org/10.3892/ijmm.2025.5655
MLA
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., Zheng, Y."Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review)". International Journal of Molecular Medicine 56.6 (2025): 214.
Chicago
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., Zheng, Y."Short‑chain fatty acids regulate hepatocellular carcinoma progression: A metabolic perspective on tumor immunity (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 214. https://doi.org/10.3892/ijmm.2025.5655
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