Background & Aims

Oxidative stress is recognized as a major driver of nonalcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, detoxification and appear therefore as attractive drug targets for the treatment of NASH.


Molecular modeling as well X-ray crystallography were used to design S217879 as a small molecule disrupting 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 (MCD) and Diet-induced Obesity NASH (DIO NASH) mouse model.


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 PBMCs. S217879 treatment for 2 weeks led in MCD mice to a dose-dependent reduction in NAFLD activity score (NAS) while significantly increasing liver Nqo1 mRNA levels, a specific NRF2 target engagement biomarker. In DIO NASH mice, S217879 treatment resulted in a significant improvement of established liver injury with clear reduction in both NAS score as well as liver fibrosis. Alpha SMA and Col1A1 staining as well as quantification of liver hydroxyproline levels confirmed the reduction in liver fibrosis in response to S217879. RNA seq analyses revealed major alterations in the liver transcriptome in response to S217879 with activation of NRF2-dependent gene transcription as well as a marked inhibition of key signaling pathways driving disease progression.


These results highlight the potential of selective disruption of NRF2-KEAP1 interaction for the treatment of NASH and liver fibrosis.

Lay summary

We report the discovery of S217879 as a potent and selective NRF2 activator with good pharmacokinetic properties. By disrupting the KEAP1-NRF2 interaction, S217879 triggers the up-regulation of the antioxidant response and the coordinated regulation of a wide spectrum of genes involved with NASH disease progression leading ultimately to the reduction of both NASH and liver fibrosis progression in mice.