A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease
Adel Hammoutène, Samira Laouirem, Miguel Albuquerque, Nathalie Colnot, Angélique Brzustowski, Dominique Valla, Nicolas Provost, Philippe Delerive, Valérie Paradis
Abstract
Background & Aims: Oxidative stress triggers metabolic-associated fatty liver disease (MAFLD) and fibrosis. Previous animal studies demonstrated that the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2), the master regulator of antioxidant response, protects against MAFLD and fibrosis. S217879, a next generation NRF2 activator has been recently shown to trigger diet-induced steatohepatitis resolution and to reduce established fibrosis in rodents. Our aim was to evaluate the therapeutic potential of S217879 in human MAFLD and its underlying mechanisms using the relevant experimental 3D model of patient-derived precision cut liver slices (PCLS). Methods: We treated PCLS from 12 patients with varying stages of MAFLD with S217879 or elafibranor (peroxisome proliferator-activated receptor [PPAR]α/δ agonist used as a referent molecule) for 2 days. Safety and efficacy profiles, steatosis, liver injury, inflammation, and fibrosis were assessed as well as mechanisms involved in MAFLD pathophysiology, namely antioxidant response, autophagy, and endoplasmic reticulum-stress. Results: ]). Such effects were mediated through an improvement of lipid metabolism, activated antioxidant response and enhanced autophagy, without effect on endoplasmic reticulum-stress. Conclusions: This study highlights the therapeutic potential of a new NRF2 activator for MAFLD using patient-derived PCLS supporting the evaluation of NRF2 activating strategies in clinical trials. Impact and implications: Oxidative stress is a major driver of metabolic-associated fatty liver disease (MAFLD) development and progression. Nuclear factor (erythroid-derived 2)-like 2, the master regulator of the antioxidative stress response, is an attractive therapeutic target for the treatment of MAFLD. This study demonstrates that S217879, a new potent and selective nuclear factor (erythroid-derived 2)-like 2 activator, displays antisteatotic effects, lowers DNA damage, apoptosis, and inflammation and inhibits fibrogenesis in human PCLS in patients with MAFLD.