Paraxonase-2 agonist, Vutiglabridin alleviates non-alcoholic steatohepatitis via autophagy activation

Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease. Glabridin, a novel anti-obesity candidate, is not druggable due to low in vivo chemical stability and bioavailability. We developed vutiglabridin (VUTI) and investigated therapeutic effects, molecular targets, and mechanisms of action in NASH. VUTI was therapeutically administrated in amylin-NASH, high fat-diet induced obesity, and thioacetamide-induced hepatic fibrosis mouse models. The mechanism of action of VUTI was studied using RNA sequencing, lipidome, and proteome analyses using mouse tissues. VUTI alleviated hepatic steatosis, fibrosis, and inflammation. Lipidome analysis revealed that VUTI affects the various individual lipid profiles. VUTI exerted therapeutic effects by increasing lipid catabolism, activating autophagy, and reducing mitochondrial oxidative stress, thus mitigating NASH pathogenesis. The cellular target of VUTI was paraoxonase-2 identified using chemical proteome analysis, which promotes its enzyme activity to enhance autophagy activation. VUTI, as a paraoxonase-2 agonist, mitigates all aspects of NASH and may be a promising therapeutic alternative for NASH. Overall design: Comparison of gene expression profiling by drug treatment of NASH liver