ArticlePloS one2018
Nrf2 protects stellate cells from Smad-dependent cell activation.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 57 citations in OpenAlex.
- Matrix stiffness shapes early transcriptional trajectories during hepatic stellate cell activation.Hepatology international · 2026Article
- Targeted Therapy for Skeletal Muscle Fibrosis: Regulation of Myostatin, TGF-β, MMP, and TIMP to Maintain Extracellular Matrix Homeostasis.Biologics : targets & therapy · 2025Review
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- Novel Strategy to Assess the Neurotoxicity of Organic Solvents Such as Glycol Ethers: Protocol for Combining In Vitro and In Silico Methods With Human-Controlled Exposure Experiments.JMIR research protocols · 2024Article
- The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases.Antioxidants (Basel, Switzerland) · 2023Review
- A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease.JHEP reports : innovation in hepatology · 2023Article
- Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice.bioRxiv : the preprint server for biology · 2023Article
- Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice.JHEP reports : innovation in hepatology · 2023Article
- Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging.Cell metabolism · 2023Article
- Mechanisms of Yajieshaba in the treatment of liver fibrosis through the Keap1-Nrf2 signaling pathway.Frontiers in pharmacology · 2023Article
- Cellular heterogeneity and plasticity during NAFLD progression.Frontiers in molecular biosciences · 2023Review
- 18β-Glycyrrhetinic Acid Protects against Cholestatic Liver Injury in Bile Duct-Ligated Rats.Antioxidants (Basel, Switzerland) · 2022Article
- D-Carvone Attenuates CClBiology · 2022Article
- Nrf2/ARE axis signalling in hepatocyte cellular death.Molecular biology reports · 2022Review
- Cigarette smoke-induced oxidative stress activates NRF2 to mediate fibronectin disorganization in vascular formation.Open biology · 2022Article
- Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease.Antioxidants (Basel, Switzerland) · 2021Review
- Article
- Article
- Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation.International journal of molecular sciences · 2021Article
- Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatic stellate cells (HSC) orchestrate the deposition of extracellular matrix (ECM) and are the primary effector of liver fibrosis. Several factors, including TGF-β1, PDGF and oxidative stress, have been shown to trigger HSC activation. However, the involvement of cellular defence mechanisms, such as the activation of antioxidant response by Nrf2/Keap1 in the modulation of HSC activation is not known. The aim of this work was to elucidate the role of Nrf2 pathway in HSC trans-differentiation involved in the development of fibrosis. To this end, we repressed Nrf2 and Keap1 expression in HSC with specific siRNAs. We then assessed activation markers, as well as proliferation and migration, in both primary and immortalised human HSCs exposed to Smad inhibitors (SB-431542 hydrate and SB-525334), TGF-β1 and/or PDGF. Our results indicate that knocking down Nrf2 induces HSC activation, as shown by an increase in αSMA-positive cells and by gene expression induction of ECM components (collagens and fibronectin). HSC with reduced Nrf2-levels also showed an increase in migration and a decrease in proliferation. We could also demonstrate that the activation of Nrf2-deficient HSC involves the TGF-β1/Smad pathway, as the activation was successfully inhibited with the two tested Smad inhibitors. Moreover, TGF-β1 elicited a stronger induction of HSC activation markers in Nrf2 deficient cells than in wild type cells. Thus, our data suggest that Nrf2 limits HSCs activation, through the inhibition of the TGF-β1/Smad pathway in HSCs.
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