PMID- 37663119 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230905 IS - 2589-5559 (Electronic) IS - 2589-5559 (Linking) VI - 5 IP - 10 DP - 2023 Oct TI - A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease. PG - 100845 LID - 10.1016/j.jhepr.2023.100845 [doi] LID - 100845 AB - 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]alpha/delta 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: Neither elafibranor nor S217879 had toxic effects at the tested concentrations on human PCLS with MAFLD. PPARalpha/delta and NRF2 target genes (pyruvate dehydrogenase kinase 4 [PDK4], fibroblast growth factor 21 [FGF21], and NAD(P)H quinone dehydrogenase 1 [NQO1], heme oxygenase 1 [HMOX1], respectively) were strongly upregulated in PCLS in response to elafibranor and S217879, respectively. Compared with untreated PCLS, elafibranor and S217879-treated slices displayed lower triglycerides and reduced inflammation (IL-1beta, IL-6, chemokine (C-C motif) ligand 2 [CCL2]). Additional inflammatory markers (chemokine (C-C motif) ligand 5 [CCL5], stimulator of interferon genes [STING], intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) were downregulated by S217879. S217879 but not elafibranor lowered DNA damage (phospho-Histone H2A.X [p-H2A.X], RAD51, X-ray repair cross complementing 1 [XRCC1]) and apoptosis (cleaved caspase-3), and inhibited fibrogenesis markers expression (alpha smooth muscle actin [alpha-SMA], collagen 1 alpha 1 [COL1A1], collagen 1 alpha 2 [COL1A2]). 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. CI - (c) 2023 The Author(s). FAU - Hammoutene, Adel AU - Hammoutene A AD - Universite Paris Cite, Inserm, Centre de Recherche sur l'inflammation, F-75018, Paris, France. AD - Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France. FAU - Laouirem, Samira AU - Laouirem S AD - Universite Paris Cite, Inserm, Centre de Recherche sur l'inflammation, F-75018, Paris, France. FAU - Albuquerque, Miguel AU - Albuquerque M AD - Universite Paris Cite, Inserm, Centre de Recherche sur l'inflammation, F-75018, Paris, France. AD - Departement de Pathologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. FAU - Colnot, Nathalie AU - Colnot N AD - Departement de Pathologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. FAU - Brzustowski, Angelique AU - Brzustowski A AD - Universite Paris Cite, Inserm, Centre de Recherche sur l'inflammation, F-75018, Paris, France. FAU - Valla, Dominique AU - Valla D AD - Universite Paris Cite, Inserm, Centre de Recherche sur l'inflammation, F-75018, Paris, France. FAU - Provost, Nicolas AU - Provost N AD - Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France. FAU - Delerive, Philippe AU - Delerive P AD - Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France. FAU - Paradis, Valerie AU - Paradis V AD - Universite Paris Cite, Inserm, Centre de Recherche sur l'inflammation, F-75018, Paris, France. AD - Departement de Pathologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. CN - QUID-NASH Research Group LA - eng PT - Journal Article DEP - 20230712 PL - Netherlands TA - JHEP Rep JT - JHEP reports : innovation in hepatology JID - 101761237 PMC - PMC10472315 OTO - NOTNLM OT - Elafibranor OT - Fibrosis OT - Inflammation OT - MAFLD OT - NASH OT - NRF2 OT - Oxidative stress OT - PCLS OT - S217879 COIS- AH was a post-doctoral researcher at Servier and Inserm. PD and NP are employees of Servier. Please refer to the accompanying ICMJE disclosure forms for further details. EDAT- 2023/09/04 06:43 MHDA- 2023/09/04 06:44 PMCR- 2023/07/12 CRDT- 2023/09/04 04:54 PHST- 2022/12/29 00:00 [received] PHST- 2023/06/09 00:00 [revised] PHST- 2023/06/20 00:00 [accepted] PHST- 2023/09/04 06:44 [medline] PHST- 2023/09/04 06:43 [pubmed] PHST- 2023/09/04 04:54 [entrez] PHST- 2023/07/12 00:00 [pmc-release] AID - S2589-5559(23)00176-3 [pii] AID - 100845 [pii] AID - 10.1016/j.jhepr.2023.100845 [doi] PST - epublish SO - JHEP Rep. 2023 Jul 12;5(10):100845. doi: 10.1016/j.jhepr.2023.100845. eCollection 2023 Oct.