GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells
Open accessAbstract
In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl 4 -treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Clearance of aHSCs from fibrotic liver through apoptosis or deactivation can promote fibrosis regression.
“Studies have shown that clearance of aHSCs from fibrotic liver through apoptosis or deactivation can promote fibrosis regression [8].”
From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [8]
A growing list of transcription factors promote the quiescent state of HSCs, including TCF21, LHX2, GATA4, and PPARγ.
“A growing list of transcription factors promote the quiescent state of HSCs, including transcription factor 21 (TCF21) (265), LIM/homeobox protein 2 (LHX2) (266), GATA binding protein 4 (GATA4) (267), and PPARγ (268).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [267]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bataller, R., & Brenner, D. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24282 · Cited by 4,958 · see citing works
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Srinivas, S., Watanabe, T., Lin, C.-S., William, C. M., Tanabe, Y., Jessell, T. M., & Costantini, F. (2001) · BMC Developmental Biology · doi:10.1186/1471-213x-1-4 · Cited by 3,121 · see citing works
Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis
Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., Benner, C., Iwaisako, K., Moore-Morris, T., Scott, B., Tsukamoto, H., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201840109 · Cited by 805 · see citing works
Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice
Troeger, J. S., Mederacke, I., Gwak, G., Dapito, D. H., Mu, X., Hsu, C. C., Pradere, J., Friedman, R. A., & Schwabe, R. F. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.06.036 · Cited by 515 · see citing works
Hepatic Stellate Cells as a Target for the Treatment of Liver Fibrosis
Bataller, R. A., & Brenner, D. A. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-17558 · Cited by 493 · see citing works
Activation of hepatic stellate cells - a key issue in liver fibrosis
Reeves, H. L. (2002) · Frontiers in bioscience · doi:10.2741/reeves · Cited by 420 · see citing works
Wong, L., Yamasaki, G., Johnson, R. J., & Friedman, S. L. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117497 · Cited by 304 · see citing works
Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis
Kisseleva, T., & Brenner, D. A. (2007) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04658.x · Cited by 286 · see citing works
Failure to prolyl hydroxylate hypoxia‐inducible factor α phenocopies VHL inactivation in vivo
Kim, W. Y., Safran, M., Buckley, M. R., Ebert, B. L., Glickman, J., Bosenberg, M., Regan, M., & Kaelin, W. G. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601300 · Cited by 235 · see citing works
Vascular Endothelial Growth Factor Promotes Fibrosis Resolution and Repair in Mice
Yang, L., Kwon, J., Popov, Y., Gajdos, G., Ordog, T., Brekken, R., Mukhopadhyay, D., Schuppan, D., Bi, Y., Simonetto, D., et al. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.01.061 · Cited by 234 · see citing works
GATA4 is a dosage-sensitive regulator of cardiac morphogenesis
Pu, W. T., Ishiwata, T., Juraszek, A. L., Ma, Q., & Izumo, S. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.08.008 · Cited by 223 · see citing works
Shayakhmetov, D. M., Li, Z.-Y., Ni, S., & Lieber, A. (2004) · Journal of Virology · doi:10.1128/jvi.78.10.5368-5381.2004 · Cited by 210 · see citing works
Liu, X., Xu, J., Rosenthal, S., Zhang, L., McCubbin, R., Meshgin, N., Shang, L., Koyama, Y., Ma, H., Sharma, S., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.027 · Cited by 205 · see citing works
Qu, A., Taylor, M. J., Xue, X., Matsubara, T., METZGER, D., Chambon, P., Gonzalez, F. J., & Shah, Y. M. (2011) · Hepatology · doi:10.1002/hep.24400 · Cited by 181 · see citing works
Dai, Y., Cserjesi, P., Markham, B. E., & Molkentin, J. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202490200 · Cited by 181 · see citing works
Géraud, C., Reiners-Koch, P.-S., Zierow, J., Klapproth, K., Busch, K., Olsavszky, V., Leibing, T., Demory, A., Ulbrich, F., Diett, M., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90086 · Cited by 164 · see citing works
Fibrogenesis of Parenchymal Organs
Kisseleva, T., & Brenner, D. A. (2008) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200711-168dr · Cited by 161 · see citing works
Copple, B. L., Bai, S., Burgoon, L. D., & Moon, J.-O. (2010) · Liver International · doi:10.1111/j.1478-3231.2010.02347.x · Cited by 153 · see citing works
Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation
Menendez-Montes, I., Escobar, B., Palacios, B., Gómez, M. J., Izquierdo-García, J. L., Flores, L., Jiménez‐Borreguero, L. J., Aragonés, J., Ruı́z-Cabello, J., Torres, M., et al. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.11.012 · Cited by 144 · see citing works
Bosse, T., Piaseckyj, C. M., Burghard, E., Fialkovich, J. J., Rajagopal, S. K., Pu, W. T., & Krasinski, S. D. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00124-06 · Cited by 142 · see citing works
Rojas, A., Kong, S. W., Agarwal, P., Gilliss, B. M., Pu, W. T., & Black, B. L. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00717-08 · Cited by 122 · see citing works
Self-citationEstrogen reduces CCL4- induced liver fibrosis in rats
Xu, J.-W. (2002) · World Journal of Gastroenterology · doi:10.3748/wjg.v8.i5.883 · Cited by 121 · cited 1× · see citing works
“Several reports have found that female rodents are more resistant to CCl4 treatment than male rodents (13, 14).”
Svensson, E. C., Huggins, G. S., Dardik, F. B., Polk, C. E., & Leiden, J. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001522200 · Cited by 120 · see citing works
Zhang, Y., Wu, L., Wang, Y., Zhang, M., Li, L., Zhu, D., Li, X., Gu, H., Zhang, C., & Zen, K. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.314922 · Cited by 107 · see citing works
Mohlin, S., Hamidian, A., von Stedingk, K., Bridges, E., Wigerup, C., Bexell, D., & Påhlman, S. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0708 · Cited by 104 · see citing works
Targeting Hypoxia Inducible Factors-1α As a Novel Therapy in Fibrosis
Xiong, A., & Liu, Y. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00326 · Cited by 102 · see citing works
Nakano, Y., Kamiya, A., Sumiyoshi, H., Tsuruya, K., Kagawa, T., & Inagaki, Y. (2020) · Hepatology · doi:10.1002/hep.30965 · Cited by 86 · see citing works
GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice
Delgado‐Sainz, I., Carrasco, M., Cano, E., Carmona, R., García‐Carbonero, R., Gómez, L. M. M., Soria, B., Martín, F., Cano, D. A., Muñoz‐Chápuli, R., et al. (2014) · Hepatology · doi:10.1002/hep.27005 · Cited by 60 · see citing works
Self-citationFunction of GATA Factors in the Adult Mouse Liver
Zheng, R., Rebolledo‐Jaramillo, B., Zong, Y., Wang, L., Russo, P., Hancock, W. W., Stanger, B. Z., Hardison, R. C., & Blobel, G. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083723 · Cited by 46 · see citing works
Cai, H., Bai, Z., & Ge, R.-L. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.01.002 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hepatic inflammatory responses in liver fibrosis
Hammerich, L., & Tacke, F. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00807-x · Cited by 803 · see citing works
Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158 · see citing works
Liver fibrosis resolution: from molecular mechanisms to therapeutic opportunities
Pei, Q., Yi, Q., & Tang, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119671 · Cited by 121 · see citing works
Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease
Wiering, L., Subramanian, P., & Hammerich, L. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.02.010 · Cited by 80 · see citing works
Shao, M., Zhang, X., Sun, J., Dong, H., Han, X., Yang, Q., Chen, R., Shen, L., Xu, L., Wang, L., et al. (2025) · Exploration · doi:10.1002/exp.70000 · Cited by 26 · see citing works
“Studies have shown that clearance of aHSCs from fibrotic liver through apoptosis or deactivation can promote fibrosis regression [8].”
Zhu, D., Sun, Z., Wei, J., Zhang, Y., An, W., Lin, Y., & Li, X. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s450284 · Cited by 17 · see citing works
- Authors
- Arroyo, N., Villamayor, L., Díaz, I., Carmona, R., Ramos-Rodríguez, M., Muñoz-Chápuli, R., Pasquali, L., Toscano, M. G., Martín, F., Cano, D. A., & Rojas, A.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Andalusian Centre for Nanomedicine and Biotechnology (ES)
- Universitat Pompeu Fabra (ES)
- Universidad de Málaga y Centro Andaluz de Nanomedicina, Málaga, Spain.
- Amarna Therapeutics, Sevilla, Spain.
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad Pablo de Olavide, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
- Corresponding author
- Rojas, Anabel
- ORCID
- Venue
- JCI Insight
- Published
- 2021-12-08
- Volume
- 6
- Issue
- 23
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8675192
- OpenAlex
- W3209127942
- Cited by
- 60
- References
- 30
- Citations by year
- 2026: 16 · 2025: 9 · 2024: 15 · 2023: 16 · 2022: 4
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- RIO (Universidad Pablo de Olavide) (submittedVersion, cc-by-nc-nd)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
- Funders
- Spanish Ministry of Economy and Competitiveness (BFU2017-83907-P)
- ISCIII-Subdirección General de Evaluación y Fomento de la Investigación co-funded with Fondos FEDER (PI16/00175)
- Agencia Andaluza del Conocimiento, Consejería de Transformación Económica, Industria, Conocimiento y Universidades (PY20_00850)
- Spanish Ministry of Economy and Innovation (BFU2017-82497-P)
- Spanish Ministry of Science and Innovation (PID2020-114656RB-I00)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- GATA4, liver fibrosis regression, hepatic stellate cells, EPAS1, HIF-2α, transcriptional repression, carbon tetrachloride-induced liver injury, fibrogenic gene expression, transcription factors
- MeSH terms
- Animals, Humans, Liver Cirrhosis, Transfection, GATA4 Transcription Factor, Mice, Hepatic Stellate Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
