ArticleGut2015
Therapeutic targeting of GSK3β enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C.
Article in Gut, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 86 citations in OpenAlex.
- Nrf2 signaling pathway and its molecular regulatory mechanism.Journal of Zhejiang University. Science. B · 2026Review
- Effect and mechanism of fisetin against the development of metabolic dysfunction-associated fatty liver disease.Scientific reports · 2025Article
- Transcriptional activation of PHKG2 by TP53 promotes ferroptosis through nuclear export of NRF2 in head and neck squamous cell carcinoma.Cell death & disease · 2025Article
- Geraniin Alleviates High-Fat Diet-Induced Atherosclerosis inFood science & nutrition · 2025Article
- Glycogen synthase kinase 3β: a key player in progressive chronic kidney disease.Clinical science (London, England : 1979) · 2025Review
- Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.Redox biology · 2025Review
- The Malignant Transformation of Viral Hepatitis to Hepatocellular Carcinoma: Mechanisms and Interventions.MedComm · 2025Review
- Gallic Acid Alleviates Cognitive Impairment by Promoting Neurogenesis via the GSK3β-Nrf2 Signaling Pathway in an APP/PS1 Mouse Model.Journal of Alzheimer's disease reports · 2024Article
- Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis.Frontiers in cell and developmental biology · 2024Review
- A state-of-the-art review on the NRF2 in Hepatitis virus-associated liver cancer.Cell communication and signaling : CCS · 2023Review
- Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.Antioxidants (Basel, Switzerland) · 2023Article
- Butyrate Ameliorates Insufficient Sleep-Induced Intestinal Mucosal Damage in Humans and Mice.Microbiology spectrum · 2023Article
- Ferroptosis as an emerging therapeutic target in liver diseases.Frontiers in pharmacology · 2023Review
- Crosstalk of ferroptosis and oxidative stress in infectious diseases.Frontiers in molecular biosciences · 2023Review
- Reciprocal REGOxidative medicine and cellular longevity · 2023Article
- Protective effect of cilostazol and verapamil against thioacetamide-induced hepatotoxicity in rats may involve Nrf2/GSK-3β/NF-κB signaling pathway.Toxicology research · 2022Article
- Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-3β axis modulation.Saudi journal of biological sciences · 2022Article
- Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis.International journal of molecular sciences · 2022Review
- Review
- Signaling Induced by Chronic Viral Hepatitis: Dependence and Consequences.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
objectiveImpaired adaptive response to oxidative injuries is a fundamental mechanism central to the pathogenesis of chronic hepatitis C (CHC). Glycogen synthase kinase (GSK) 3β is an indispensable regulator of the oxidative stress response. However, the exact role of GSK3β in CHC is uncertain and was examined.
designGSK3β and Nrf2 signalling pathways were examined in JFH1 HCV infected Huh7.5.1 hepatocytes, and also in liver biopsy specimens from CHC patients.
resultsHCV infection elicited prominent Nrf2 antioxidant response in hepatocytes, marked by elevated expression of the Nrf2-dependent molecule haem oxygenase-1 and subsequent protection from apoptotic cell death. Inhibitory phosphorylation of GSK3β seems to be essential and sufficient for HCV-induced Nrf2 response. Mechanistically, GSK3β associated and physically interacted with Nrf2 in hepatocytes. In silico analysis revealed that Nrf2 encompasses multiple GSK3β phosphorylation consensus motifs, denoting Nrf2 as a cognate substrate of GSK3β. In the presence of TGFβ1, the HCV-induced GSK3β phosphorylation was blunted via a protein phosphatase 1-dependent mechanism and the cytoprotective Nrf2 response drastically impaired. This effect was counteracted by lithium, a selective inhibitor of GSK3β. In liver biopsy specimens from CHC patients, the expression of phosphorylated GSK3β positively correlated with Nrf2 expression and was inversely associated with the degree of liver injury. Moreover, CHC patients who received long-term lithium carbonate therapy primarily for concomitant psychiatric disorders exhibited much less liver injury, associated with enhanced hepatic expression of Nrf2.
conclusionsInhibition of GSK3β exerts hepatoprotection in CHC possibly through its direct regulation of Nrf2 antioxidant response.
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