A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease

Background and aimsOxidative stress triggers metabolic fatty liver disease (MAFLD) fibrosis. Previous animal studies demonstrated that the transcription factor NRF2, master regulator of antioxidant response, protects against MAFLD S217879, a next generation NRF2 activator has been recently shown to trigger diet-induced steatohepatitis resolution reduce established fibrosis in rodents. Our aim was evaluate therapeutic potential S217879 human its underlying mechanisms using relevant experimental 3D model patient-derived precision cut slices (PCLS).MethodsWe treated PCLS from 12 patients with varying stages or Elafibranor (PPARα/δ agonist used as referent molecule) for two days. Safety efficacy profiles, steatosis, injury, inflammation were assessed well involved pathophysiology, namely autophagy ER-stress.ResultsNeither nor had toxic effects at tested concentrations on MAFLD. PPARα/δ target genes (PDK4, FGF21 NQO1, HMOX1, respectively) strongly upregulated response respectively. Compared untreated PCLS, S217879-treated displayed lower triglycerides reduced (IL-1β, IL-6, CCL2). Additional inflammatory markers (CCL5, STING, ICAM-1, VCAM-1) downregulated by S217879. but not lowered DNA damages (p-H2A.X, RAD51, XRCC1) apoptosis (cleaved Caspase-3), inhibited fibrogenesis expression (α-SMA, COL1A1, COL1A2). Such mediated through an improvement lipid metabolism, activated enhanced autophagy, without effect ER-stress.ConclusionThis study highlights new supporting evaluation activating strategies clinical trials.