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Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery

  • Authors:
    • Haiyang Peng
    • Zhiyong Chen
    • Qiwei Zhang
    • Yuezhou Zhang
    • Peng Yang
    • Jianping Gong
    • Andong Zhao
  • View Affiliations / Copyright

    Affiliations: Department of Hepatobiliary Surgery, Second Hospital Affiliated to Chongqing Medical University, Chongqing 400010, P.R. China, Centre for Lipid Research and Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Hospital Affiliated to Chongqing Medical University, Chongqing 400010, P.R. China
    Copyright: © Peng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 89
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    Published online on: January 13, 2026
       https://doi.org/10.3892/mmr.2026.13799
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Abstract

Termination of liver regeneration is important for restoring hepatic function after partial hepatectomy (PHx); however, its regulatory mechanisms remain poorly understood. The present study aimed to investigate the role of collagen III (col3) in terminating liver regeneration and its interaction with the β‑catenin signaling pathway. Initially, a 2/3 PHx mouse model was established, and col3 expression dynamics were examined via immunofluorescence and reverse transcription‑quantitative PCR. Collagenase III, also known as matrix metalloproteinase‑13, was used to degrade col3 during the termination phase of liver regeneration, and the resulting effects on hepatocyte proliferation, β‑catenin signaling and liver function were assessed. Methyl‑sulfonyl AB (MSAB), a β‑catenin inhibitor, was used to explore pathway involvement. The present study demonstrated that col3 expression in the parenchymal areas of the liver was decreased during the proliferation phase and increased during the termination phase. Collagenase‑induced col3 degradation enhanced hepatocyte proliferation, delayed regenerative termination, activated β‑catenin signaling, and impaired hepatocyte differentiation and liver function. Administration of MSAB rescued these effects, partially restoring termination and function. In conclusion, col3 may regulate the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery. These findings provide new insights into collagen‑induced regulation of liver regeneration and potential therapeutic targets for optimizing hepatic recovery.

View Figures

Figure 1

Liver regeneration at different time
points after PHx in mice. (A) Body weights of mice at varying time
points post-PHx. (B) Liver-to-body weight ratio of mice at varying
time points post-PHx. (C) EdU staining of mice livers at varying
time points post-PHx. Scale bar, 50 µm. **P<0.01, ***P<0.001
and ****P<0.0001 vs. 0 h group or as indicated. ns, not
significant; PHx, partial hepatectomy.

Figure 2

Expression of collagens and related
proteins after partial hepatectomy in mice. IF staining of (A)
collagen I, (B) desmin and (C) α-SMA. Scale bar, 50 µm (×200
magnification) and 20 µm (×400 magnification). IF,
immunofluorescence; α-SMA, α-smooth muscle actin.

Figure 3

Protein and mRNA expression of
collagen III after PHx in mice. (A) IF staining of collagen III.
Scale bar, 50 µm (×200 magnification) and 20 µm (×400
magnification). (B) Relative fluorescence intensity of collagen III
in parenchymal areas. (C) Reverse transcription-quantitative PCR
analysis of Col3a1 mRNA levels. *P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001. PHx, partial hepatectomy;
col3a1, collagen III α1.

Figure 4

Liver regeneration status after
collagen III degradation during the termination phase of liver
regeneration. (A) Body weight of mice. (B) Liver-to-body weight
ratio of mice. (C) Dual IF staining of EdU and Ki-67. (D) Dual IF
staining of EdU and collagen III. Scale bars, 100 and 10 µm.
*P<0.05, **P<0.01 and ***P<0.001. ns, not significant;
PHx, partial hepatectomy; IF, immunofluorescence; Coln0.1, low-dose
collagenase III; Coln0.2, high-dose collagenase III; Col III,
collagen III.

Figure 5

Assessment of major organ injury
following administration of collagenase III. (A) Hematoxylin and
eosin staining of heart, liver, spleen, lung and kidney tissues.
Magnification, ×100. (B) Serum markers of liver and kidney
function. ns, not significant; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; BUN, blood urea nitrogen.

Figure 6

Inhibition of β-catenin partially
rescues impaired regeneration termination and liver dysfunction
induced by collagen III degradation. (A) Schematic diagram of the
animal experimental protocol; created with BioGDP.com (agreement
no. GDP2025X2AT2F) (35). (B) WB
analysis of β-catenin after collagen III degradation. (C) Body
weight and (D) liver-to-body weight ratio of mice following
collagen III degradation and β-catenin inhibition. (E) Dual
immunofluorescence staining of EdU and collagen III following
collagen III degradation and β-catenin inhibition. Scale bars, 100
and 10 µm. (F) Serum liver function marker levels following
collagen III degradation and β-catenin inhibition. (G) WB analysis
of HNF4α following collagen III degradation and β-catenin
inhibition. (H) WB analysis of cyclin D1 following collagen III
degradation and β-catenin inhibition. *P<0.05, **P<0.01 and
***P<0.001. ns, not significant; WB, western blot; PHx, partial
hepatectomy; MSAB, methyl-sulfonyl AB; Coln0.1, low-dose
collagenase III; Coln0.2, high-dose collagenase III; Col III,
collagen III; ALT, alanine aminotransferase; HNF4α, hepatocyte
nuclear factor 4α.
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Copy and paste a formatted citation
Spandidos Publications style
Peng H, Chen Z, Zhang Q, Zhang Y, Yang P, Gong J and Zhao A: <p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>. Mol Med Rep 33: 89, 2026.
APA
Peng, H., Chen, Z., Zhang, Q., Zhang, Y., Yang, P., Gong, J., & Zhao, A. (2026). <p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>. Molecular Medicine Reports, 33, 89. https://doi.org/10.3892/mmr.2026.13799
MLA
Peng, H., Chen, Z., Zhang, Q., Zhang, Y., Yang, P., Gong, J., Zhao, A."<p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>". Molecular Medicine Reports 33.3 (2026): 89.
Chicago
Peng, H., Chen, Z., Zhang, Q., Zhang, Y., Yang, P., Gong, J., Zhao, A."<p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>". Molecular Medicine Reports 33, no. 3 (2026): 89. https://doi.org/10.3892/mmr.2026.13799
Copy and paste a formatted citation
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Spandidos Publications style
Peng H, Chen Z, Zhang Q, Zhang Y, Yang P, Gong J and Zhao A: <p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>. Mol Med Rep 33: 89, 2026.
APA
Peng, H., Chen, Z., Zhang, Q., Zhang, Y., Yang, P., Gong, J., & Zhao, A. (2026). <p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>. Molecular Medicine Reports, 33, 89. https://doi.org/10.3892/mmr.2026.13799
MLA
Peng, H., Chen, Z., Zhang, Q., Zhang, Y., Yang, P., Gong, J., Zhao, A."<p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>". Molecular Medicine Reports 33.3 (2026): 89.
Chicago
Peng, H., Chen, Z., Zhang, Q., Zhang, Y., Yang, P., Gong, J., Zhao, A."<p>Collagen III regulates the termination of liver regeneration by suppressing hepatocyte proliferation and promoting functional recovery</p>". Molecular Medicine Reports 33, no. 3 (2026): 89. https://doi.org/10.3892/mmr.2026.13799
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