Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice.

Klaus Seedorf, Csaba Weber,Cedric Vinson, Sylvie Berger,Laurent-Michel Vuillard, Arpad Kiss,Stephanie Creusot,Olivier Broux, Anne Geant, Catherine Ilic,Karine Lemaitre, Johann Richard,Adel Hammoutene, Julien Mahieux, Virginie Martiny, Didier Durand, Fabien Melchiore,Miklos Nyerges,Valerie Paradis,Nicolas Provost, Valérie Duvivier,Philippe Delerive

JHEP reports : innovation in hepatology（2023）

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摘要

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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关键词

4-HNE, 4-hydroxynonenal,ARE, antioxidant response element,DIO, diet-induced obesity,GSEA, Gene Set Enrichment Analysis,HEC, hydroxyethyl cellulose,HSCs, Hepatic Stellate Cells,KEAP1, Kelch-like ECH associated protein 1,LPS, lipopolysaccharide,MCDD, methionine- and choline-deficient diet,NAFLD, non-alcoholic fatty liver disease,NAS, NAFLD activity score,NASH,NASH, non-alcoholic steatohepatitis,NRF2,NRF2, nuclear factor erythroid 2–related factor 2,PPI, Protein-protein interaction,PSR, Picrosirius red,ROS, reactive oxygen species,fibrosis,hPBMCs, human peripheral blood mononuclear cells,oxidative stress

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