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Review Open Access

Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review)

  • Authors:
    • Yiwei Wang
    • Chengyan Zhang
    • Haonan Wang
    • Yali Zhou
    • Yuanbo Yu
    • Hui Liu
    • Chuansha Gu
  • View Affiliations / Copyright

    Affiliations: Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, Department of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453700, P.R. China, Henan Key Laboratory of Immunology and Targeted Drugs, School of Medical Technology, Henan Medical University, Xinxiang, Henan 453003, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 33
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    Published online on: November 14, 2025
       https://doi.org/10.3892/ol.2025.15386
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Abstract

Neutrophil extracellular traps (NETs) are web‑like structures released by activated neutrophils, composed of DNA, histones and antimicrobial proteins. Although initially discovered for their role in innate immunity, NETs are also closely associated with the pathogenesis of chronic hepatitis and hepatocellular carcinoma (HCC). The present review, which analyzes the latest research from databases such as PubMed and Web of Science, focuses on the formation of NETs, their roles in hepatitis (including hepatitis B, non-alcoholic steatohepatitis and ischemia‑reperfusion injury) and their contributions to the initiation, progression and metastasis of HCC. The present review aimed to systematically elucidate the role of NETs in the transition from hepatitis to HCC, with a focus on underlying molecular mechanisms and potential therapeutic implications. The current findings suggest that targeting NET formation or function through inhibition of peptidylarginine deiminase 4, neutrophil elastase, DNase I or related signaling pathways may represent a promising therapeutic strategy to suppress inflammation‑driven hepatocarcinogenesis and improve outcomes for patients with HCC. However, further validation is required to translate these findings into clinical applications.
View Figures

Figure 1

Neutrophils are capable of forming
NETs via the NADPH oxidase-dependent NETosis pathway. Furthermore,
NETosis can also occur independently of NADPH oxidase activity.
Under specific conditions, neutrophils can release NETs composed of
mitochondrial DNA, particularly when mitochondrial oxidative
respiration produces substantial levels of reactive oxygen species.
The figure was drawn using Figdraw (https://www.figdraw.com/static/index.html#/). NETs,
neutrophil extracellular traps.

Figure 2

Interplay between NETs and HBV, HIRI,
NASH and HCC. Hepatic inflammations such as HBV, HIRI and NASH can
promote the formation of NETs by neutrophils; this may therefore
promote the development of HCC. The figure was drawn using Figdraw
(https://www.figdraw.com/static/index.html#/). NETs,
neutrophil extracellular traps; HBV, hepatitis B virus; HIRI,
hepatic ischemia-reperfusion injury; HCC, hepatocellular carcinoma;
NASH, non-alcoholic steatohepatitis; IL, interleukin; ROS, reactive
oxygen species; TLR, Toll-like receptor; MMP9, matrix
metallopeptidase 9; NE, neutrophil elastase; Treg, regulatory T
cell; FFA, free fatty acids; CG, cholyglycine; MCOLN3, mucolipin
TRP cation channel 3; RAGE, receptor for advanced glycation end
products; FGL2, fibrinogen-like protein 2; HMGB1, high mobility
group box 1.

Figure 3

NETs notably contribute to the
advancement of liver cancer. NETs are markedly upregulated in
hepatic malignancies, where they not only facilitate the
establishment of a tumor-supportive microenvironment but also
directly enhance the proliferation and metastatic potential of HCC
cells. The figure was drawn using Figdraw (https://www.figdraw.com/static/index.html#/).
HCC, hepatocellular carcinoma; NETs, neutrophil extracellular
traps; EMT, epithelial-mesenchymal transition; TLR, Toll-like
receptor; IL, interleukin.

Figure 4

NETs promote the transformation of
hepatitis into HCC. NETs can promote the transformation of HBV,
AFL, NASH and HIRI to HCC. The figure was drawn using Figdraw
(https://www.figdraw.com/static/index.html#/). HCC,
hepatocellular carcinoma; NETs, neutrophil extracellular traps;
TLR, Toll-like receptor; IL, interleukin; LPS, lipopolysaccharide;
HBV, hepatitis B virus; AFL, alcoholic fatty liver; NASH,
non-alcoholic steatohepatitis; HIRI, hepatic ischemia-reperfusion
injury; DAMPs, damage-associated molecular patterns; RAGE, receptor
for advanced glycation end products.
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Copy and paste a formatted citation
Spandidos Publications style
Wang Y, Zhang C, Wang H, Zhou Y, Yu Y, Liu H and Gu C: Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review). Oncol Lett 31: 33, 2026.
APA
Wang, Y., Zhang, C., Wang, H., Zhou, Y., Yu, Y., Liu, H., & Gu, C. (2026). Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review). Oncology Letters, 31, 33. https://doi.org/10.3892/ol.2025.15386
MLA
Wang, Y., Zhang, C., Wang, H., Zhou, Y., Yu, Y., Liu, H., Gu, C."Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review)". Oncology Letters 31.1 (2026): 33.
Chicago
Wang, Y., Zhang, C., Wang, H., Zhou, Y., Yu, Y., Liu, H., Gu, C."Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review)". Oncology Letters 31, no. 1 (2026): 33. https://doi.org/10.3892/ol.2025.15386
Copy and paste a formatted citation
x
Spandidos Publications style
Wang Y, Zhang C, Wang H, Zhou Y, Yu Y, Liu H and Gu C: Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review). Oncol Lett 31: 33, 2026.
APA
Wang, Y., Zhang, C., Wang, H., Zhou, Y., Yu, Y., Liu, H., & Gu, C. (2026). Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review). Oncology Letters, 31, 33. https://doi.org/10.3892/ol.2025.15386
MLA
Wang, Y., Zhang, C., Wang, H., Zhou, Y., Yu, Y., Liu, H., Gu, C."Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review)". Oncology Letters 31.1 (2026): 33.
Chicago
Wang, Y., Zhang, C., Wang, H., Zhou, Y., Yu, Y., Liu, H., Gu, C."Research progress on neutrophil extracellular traps and hepatitis‑to‑hepatocellular carcinoma transformation (Review)". Oncology Letters 31, no. 1 (2026): 33. https://doi.org/10.3892/ol.2025.15386
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