CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice
Abstract
Background and aims STAT3, a member of the signal transducer and activator of transcription (STAT) family, is strongly associated with liver injury, inflammation, regeneration, and hepatocellular carcinoma development. However, the signals that regulate STAT3 activity are not completely understood. Approach and results Here we characterize CREB/ATF bZIP transcription factor CREBZF as a critical regulator of STAT3 in the hepatocyte to repress liver regeneration. We show that CREBZF deficiency stimulates the expression of the cyclin gene family and enhances liver regeneration after partial hepatectomy. Flow cytometry analysis reveals that CREBZF regulates cell cycle progression during liver regeneration in a hepatocyte-autonomous manner. Similar results were observed in another model of liver regeneration induced by intraperitoneal injection of carbon tetrachloride (CCl 4 ). Mechanistically, CREBZF potently associates with the linker domain of STAT3 and represses its dimerization and transcriptional activity in vivo and in vitro. Importantly, hepatectomy-induced hyperactivation of cyclin D1 and liver regeneration in CREBZF liver-specific knockout mice was reversed by selective STAT3 inhibitor cucurbitacin I. In contrast, adeno-associated virus-mediated overexpression of CREBZF in the liver inhibits the expression of the cyclin gene family and attenuates liver regeneration in CCl 4 -treated mice. Conclusions These results characterize CREBZF as a coregulator of STAT3 to inhibit…
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Increased tyrosine 705 phosphorylation of STAT3 in liver fibrosis can promote HSC proliferation and activation and contribute to liver fibrogenesis.
“Previous researchers have observed increased tyrosine 705 (Tyr 705) phosphorylation of STAT3 in liver fibrosis, which can promote HSC proliferation and activation and contribute to liver fibrogenesis [21, 22].”
From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [21]
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References 50 · Cited by 65
- Authors
- Hu, Z., Han, Y., Liu, Y., Zhao, Z., Ma, F., Cui, A., Zhang, F., Liu, Z., Xue, Y., Bai, J., Wu, H., Bian, H., Chin, Y. E., Yu, Y., Meng, Z., Wang, H., Liu, Y., Fan, J., Gao, X., Chen, Y., & Li, Y.
- Affiliations
- Shanghai Institute of Nutrition and Health (CN)
- Wuhan University (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Soochow University (CN)
- Tianjin Medical University (CN)
- Department of Pathology and Pathophysiology,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China
- Anhui Medical University (CN)
- Chinese Academy of Sciences (CN)
- Department of Gastroenterology,Xinhua Hospital, Shanghai Jiaotong University School of Medicine,Shanghai,China
- Corresponding author
- Li, Yu
- ORCID
- Venue
- Hepatology
- Published
- 2020-01-24
- Volume
- 71
- Issue
- 4
- Pages
- 1421-1436
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2970782573
- Cited by
- 65
- References
- 50
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 16 · 2023: 15 · 2022: 8 · 2021: 8 · 2020: 2 · 2019: 1 · 2012: 1
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31471129, 31671224)
- Chinese Academy of Sciences (KJZD‐EW‐G20‐02)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- STAT3, liver regeneration, hepatocyte cell cycle, cyclin D1, STAT3 dimerization, partial hepatectomy, carbon tetrachloride, cucurbitacin I
- MeSH terms
- Animals, Carbon Tetrachloride, Cell Cycle, Gene Expression Regulation, Liver, Liver Regeneration, Gene Deletion, Mice, Knockout, Hepatocytes, STAT3 Transcription Factor, Basic-Leucine Zipper Transcription Factors, Mice, Metabolic Networks and Pathways
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