ArticleJHEP reports : innovation in hepatology2023
Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice.
Article in JHEP reports : innovation in hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- A systematic review of the anti-inflammatory and anti-fibrotic potential of human umbilical cord mesenchymal stem cells-derived exosomes in experimental models of liver regeneration.Molecular biology reports · 2024Pooled it
- Cysteine-based molecular switches: a focus on KEAP1 and BACH1 in regulating the antioxidant response.Archives of toxicology · 2026Review
- Molecular mechanisms and pathogenesis of MASH.Nature · 2026Review
- OMA1 protects from liver injury and tumorigenesis during aging by controlling hepatic immunogenicity.The EMBO journal · 2026Article
- Alisol F 24-acetate attenuated metabolic dysfunction-associated steatohepatitis by targeting the KEAP1/NRF2-mediated macrophage pyroptosis.Chinese medicine · 2026Article
- Time-dependent modulation of FXR and Nrf2 signaling in rat models of BDL-induced cholestasis.Iranian journal of basic medical sciences · 2026Article
- Periodontitis and MASLD: a narrative review of the direct oral-hepatic pathway.Frontiers in cellular and infection microbiology · 2026Review
- Discovery of a novel Keap1 inhibitor for neurodegeneration through virtual screening and molecular dynamics simulations.PloS one · 2026Article
- Pharmacological Targeting of NRF2 Represents a Promising Therapeutic Approach for Pyroptosis-Related Non-Alcoholic Fatty Liver Disease.Current medicinal chemistry · 2026Review
- Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Targeting NOTCH1-KEAP1 axis retards chronic liver injury and liver cancer progression via regulating stabilization of NRF2.Journal of experimental & clinical cancer research : CR · 2025Article
- A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy.Journal of biomedical science · 2025Article
- Role of amino acids in the regulation of hepatic gluconeogenesis and lipogenesis in metabolic dysfunctionassociated steatotic liver disease.Clinical and molecular hepatology · 2025Review
- Buddleoside alleviates nonalcoholic steatohepatitis by targeting the AMPK-TFEB signaling pathway.Autophagy · 2025Article
- Gelsolin's Protective Role in MASH through F-Actin Regulation and P53 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Bioinformatics-Guided Experimental Validation Identifies NQO1 as a Senescence-Ferroptosis Hub in Liver Fibrosis.Biomedicines · 2025Article
- Differences in Fatty Acid Metabolism between MCDD and HFD Induced Metabolic Dysfunction-associated Fatty Liver Disease Model Mice.Biological procedures online · 2025Article
- Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.Redox biology · 2025Review
- Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.Redox biology · 2025Review
- Melissa officinalis extract palliates redox imbalance and inflammation associated with hyperthyroidism-induced liver damage by regulating Nrf-2/ Keap-1 gene expression in γ-irradiated rats.BMC complementary medicine and therapies · 2024Article
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background & Aims: Oxidative stress is recognized as a major driver of non-alcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, as well as detoxification, and thus appear to be attractive targets for the treatment of NASH. Methods: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction. S217879 was highly characterized using various molecular and cellular assays. It was then evaluated in two different NASH-relevant preclinical models, namely the methionine and choline-deficient diet (MCDD) and diet-induced obesity NASH (DIO NASH) models. Results: Molecular and cell-based assays confirmed that S217879 is a highly potent and selective NRF2 activator with marked anti-inflammatory properties, as shown in primary human peripheral blood mononuclear cells. In MCDD mice, S217879 treatment for 2 weeks led to a dose-dependent reduction in NAFLD activity score while significantly increasing liver Conclusions: These results highlight the potential of selective disruption of the NRF2-KEAP1 interaction for the treatment of NASH and liver fibrosis. Impact and implications: We report the discovery of S217879 - a potent and selective NRF2 activator with good pharmacokinetic properties. By disrupting the KEAP1-NRF2 interaction, S217879 triggers the upregulation of the antioxidant response and the coordinated regulation of a wide spectrum of genes involved in NASH disease progression, leading ultimately to the reduction of both NASH and liver fibrosis progression in mice.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.