PE-208 : Complementary Liver Histological Effects of Mitochondrial Function Enhancer HSG4112, a Synthetic First-in-Class Small Molecule, and Semaglutide in a Diet-Induced and Biopsy-Confirmed Obese Mouse Model of Non-Alcoholic Steatohepatitis

Aims: HSG4112, a synthetic new chemical entity, is a first-inclass oral small molecule in clinical development for obesity. In preclinical studies, HSG4112 as mitochondrial function enhancer has been demonstrated to increase energy expenditure and decrease chronic low-grade inflammation, resulting in reduced adiposity and robust weight loss. As these therapeutic effects are highly relevant for the management of non-alcoholic steatohepatitis (NASH), we aimed to compare the therapeutic effects of HSG4112 and semaglutide (GLP-1 receptor agonist) in a diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Methods: Male C57BL/6JRj mice were fed AMLN diet high in trans-fat, fructose and cholesterol for 35 weeks. Only animals with liver biopsy-confirmed steatosis (score ≥2) and fibrosis (stage ≥F1) were included and stratified into treatment groups according to baseline body weight and liver collagen-1a1 deposition. DIO-NASH mice received vehicle (PO, QD), HSG4112 (50 or 100 mg/kg, PO, QD), or semaglutide (30 nmol/kg, SC, QD) for 10 weeks. Endpoints included within-subject changes in body composition, NAFLD Activity Score (NAS) and fibrosis stage as well as terminal quantitative liver histology and transcriptome analysis. Results: HSG4112 and semaglutide induced similar reductions in body weight (20%) and whole-body fat levels (10-12%) in DIO-NASH mice. These metabolic effects were accompanied by significantly reduced plasma levels of liver injury markers (ALT, AST, ALP). Notably, in contrast to semaglutide, HSG4112 did not reduce any food intake and improved NAS by a different mode of action. Accordingly, HSG4112 specifically attenuated lobular inflammation while semaglutide reduced steatosis severity. Both compounds significantly reduced fibrogenesis activity associated with suppressed stellate cell activation and lowered collagen mRNA expression. Conclusions: HSG4112 showed robust anti-obesity and anti- NASH efficacy, especially with reduced liver inflammation and fibrogenesis, in DIO-NASH mice with biopsy-confirmed liver pathology. While its efficacy was comparable to that of semaglutide, HSG4112 did not reduce food intake, further demonstrating its energy expenditure-enhancing effect. These findings suggest HSG4112 as a potent novel drug for the treatment of NASH.