Zfp697/ZNF697 is an RNA-binding protein that modulates TGF-β1 signaling and hepatic inflammation in liver disease
11 affiliations
- 1Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, Stockholm, SE-171 77, Sweden
- 2Department of Pharmacology and Stanley & Judith Frankel Institute for Heart & Brain Health, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- 3Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
- 4Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA
- 5Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
- 6Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA
- 7Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
- 8Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, 70210 Kuopio, Finland
- 9Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Wellbeing Services County of North Savo, 70210 Kuopio, Finland
- 10Central European Institute of Technology, CEITEC, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
- 11National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
Abstract
Liver diseases driven by metabolic dysfunction, inflammation, and fibrosis such as metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injury represent a growing global health burden. The zinc finger protein Zfp697 (ZNF697 in humans) is a newly identified regulator of inflammation and regeneration in skeletal muscle. Here, we characterize the role of liver Zfp697 and show that its expression is increased in multiple animal models of liver disease. Indeed, Zfp697/ZNF697 transcript levels show a strong positive correlation with several markers of liver inflammation and fibrosis. In line with that, in human and mouse hepatocytes TGF-β1 increases Zfp697 expression, which in turn regulates genes involved in TGF-β1 signaling, chemokine secretion, and immune cell recruitment. In mice, hepatocyte-specific Zfp697 deletion improves glucose tolerance and is associated with the absence of MASH-induced lean mass loss but does not confer uniform hepatoprotection. Biochemical purification of Zfp697 protein interactors and enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that Zfp697 interacts with other RNA-binding proteins and associates with over 1,000 RNAs in mouse liver. Zfp697-associated RNAs include several transcript types, with a large representation of mRNAs which group in pathways related to transcriptional regulation, PI3K/AKT signaling, and cell differentiation. These findings identify Zfp697 as a novel RNA-interacting protein and modulator of TGF-β signaling in the liver and provide a basis for further investigation of its role in liver disease.
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BibTeX
@article{præstholm2026zfp697znf697,
title = {{Zfp697/ZNF697 is an RNA-binding protein that modulates TGF-β1 signaling and hepatic inflammation in liver disease}},
author = {Stine M. Præstholm and Jorge C. Correia and Rafael Hoyos Justiniano and Alisson L. da Rocha and Aurel B. Leuchtmann and Tadas Sereiva and Margareta Porsmyr-Palmertz and Kathrine Rothamel and Dorota Kaminska and Ranjani Sri Ganji and David Potěšil and Zbyněk Zdráhal and Jussi Pihlajamäki and Gene W. Yeo and Jorge L. Ruas},
journal = {Molecular Metabolism},
year = {2026},
month = oct,
doi = {10.1016/j.molmet.2026.102457},
url = {https://doi.org/10.1016/j.molmet.2026.102457},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Zfp697/ZNF697 is an RNA-binding protein that modulates TGF-β1 signaling and hepatic inflammation in liver disease
AU - Stine M. Præstholm
AU - Jorge C. Correia
AU - Rafael Hoyos Justiniano
AU - Alisson L. da Rocha
AU - Aurel B. Leuchtmann
AU - Tadas Sereiva
AU - Margareta Porsmyr-Palmertz
AU - Kathrine Rothamel
AU - Dorota Kaminska
AU - Ranjani Sri Ganji
AU - David Potěšil
AU - Zbyněk Zdráhal
AU - Jussi Pihlajamäki
AU - Gene W. Yeo
AU - Jorge L. Ruas
PY - 2026
DA - 2026/10/14
JO - Molecular Metabolism
DO - 10.1016/j.molmet.2026.102457
UR - https://doi.org/10.1016/j.molmet.2026.102457
AB - Liver diseases driven by metabolic dysfunction, inflammation, and fibrosis such as metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injury represent a growing global health burden. The zinc finger protein Zfp697 (ZNF697 in humans) is a newly identified regulator of inflammation and regeneration in skeletal muscle. Here, we characterize the role of liver Zfp697 and show that its expression is increased in multiple animal models of liver disease. Indeed, Zfp697/ZNF697 transcript levels show a strong positive correlation with several markers of liver inflammation and fibrosis. In line with that, in human and mouse hepatocytes TGF-β1 increases Zfp697 expression, which in turn regulates genes involved in TGF-β1 signaling, chemokine secretion, and immune cell recruitment. In mice, hepatocyte-specific Zfp697 deletion improves glucose tolerance and is associated with the absence of MASH-induced lean mass loss but does not confer uniform hepatoprotection. Biochemical purification of Zfp697 protein interactors and enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that Zfp697 interacts with other RNA-binding proteins and associates with over 1,000 RNAs in mouse liver. Zfp697-associated RNAs include several transcript types, with a large representation of mRNAs which group in pathways related to transcriptional regulation, PI3K/AKT signaling, and cell differentiation. These findings identify Zfp697 as a novel RNA-interacting protein and modulator of TGF-β signaling in the liver and provide a basis for further investigation of its role in liver disease.
SN - 2212-8778
ER -