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Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo
Open accessAbstract
Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Homologs of NADPH oxidases (NOXs) are major sources of ROS, but the exact role of the individual homologs in liver disease is unknown. Our goal was to determine the role of NOX4 in liver fibrosis induced by bile duct ligation (BDL) with the aid of the pharmacological inhibitor GKT137831, and genetic deletion of NOX4 in mice. GKT137831 was either applied for the full term of BDL (preventive arm) or started at 10 day postoperatively (therapeutic arm). Primary hepatic stellate cells (HSC) from control mice with and without BDL were analyzed and the effect of NOX4 inhibition on HSC activation was also studied. FasL or TNFα/actinomycin D-induced apoptosis was studied in wild-type and NOX4(-/-) hepatocytes. NOX4 was upregulated by a TGF-β/Smad3-dependent mechanism in HSC. Downregulation of NOX4 decreased ROS production and the activation of NOX4(-/-) HSC was attenuated. NOX4(-/-) hepatocytes were more resistant to FasL or TNFα/actinomycin D-induced apoptosis. Similarly, after pharmacological NOX4 inhibition, ROS production, the expression of fibrogenic markers, and hepatocyte apoptosis were reduced. NOX4 was expressed in human livers with stage 2-3 autoimmune hepatitis. Fibrosis was attenuated by the genetic deletion of NOX4. BDL mice gavaged with GKT137831 in the preventive or the therapeutic arm displayed less ROS production, significantly attenuated fibrosis, and decreased hepatocyte apoptosis. In conclusion, NOX4 plays a key role in liver fibrosis. GKT137831 is a potent inhibitor of fibrosis and hepatocyte apoptosis; therefore, it is a promising therapeutic agent for future translational studies.
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“GKT-136901 and GKT-137831 (FIGURE 10) are the first inhibitors suitable for oral administration, and currently GKT-137831 is in phase 2 clinical trials (472).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [472]
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Metadata
- Authors
- Jiang, J. X., Chen, X., Serizawa, N., Szyndralewiez, C., Page, P., Schröder, K., Brandes, R. P., Devaraj, S., & Török, N. J.
- Affiliations
- UC Davis Health (US)
- Genkyotex (Switzerland) (CH)
- Goethe University Frankfurt (DE)
- University of California Davis Medical Center (US)
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 53
- Issue
- 2
- Pages
- 289-296
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC3392471
- OpenAlex
- W2081975963
- Cited by
- 251
- References
- 26
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 3 · 2023: 24 · 2022: 15 · 2021: 18 · 2020: 17 · 2019: 15 · 2018: 13 · 2017: 21 · 2016: 20 · 2015: 33 · 2014: 21 · 2013: 20 · 2012: 7
- FWCI
- 16.41
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK083283, DK-083283, R01DK083283)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- liver fibrosis, hepatocyte apoptosis, GKT137831, NADPH oxidase, reactive oxygen species, bile duct ligation, hepatic stellate cell activation, TGF-β/Smad3 signaling, TNFα-induced apoptosis, autoimmune hepatitis, chronic liver injury
- MeSH terms
- NADPH Oxidase 1, NADPH Oxidase 4, Animals, Bile Ducts, Dactinomycin, Humans, Ligation, Liver, Liver Cirrhosis, NADH, NADPH Oxidoreductases, Pyrazoles, Pyridines, Pyridones, Signal Transduction, Transforming Growth Factor beta, Apoptosis, Gene Deletion, Reactive Oxygen Species, NADPH Oxidases, Hepatitis, Autoimmune, Hepatocytes, Pyrazolones, Mice, Rats, Smad3 Protein, Fas Ligand Protein, Hepatic Stellate Cells
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