Original Abstract

AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited effective treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise for metabolic and hepatic benefits. This study evaluated the therapeutic efficacy of Efsubaglutide Alfa, a novel long-acting GLP-1RA, in a mouse model of MASH. MATERIALS AND METHODS: Male C57BL/6J mice with diet-induced obesity received a high-fat diet and low-dose CCl4 injections to induce MASH. Mice were randomized to receive vehicle, obeticholic acid (OCA), semaglutide or Efsubaglutide Alfa at low, medium or high doses for 42 days. Endpoints included liver histology, collagen quantification by second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) imaging, and serum liver enzymes, lipids and metabolic parameters. RESULTS: By day 41, Efsubaglutide Alfa produced dose-dependent reductions in body weight, liver weight and liver-to-body weight ratio versus MASH controls (all p < 0.01). Histology showed reduced steatosis and lowered the NAFLD Activity Scores (NAS), with high-dose treatment achieving a NAS of 3.0 ± 0.47 versus 4.5 ± 0.22 in MASH controls (p < 0.01). Although Sirius Red-based fibrosis area and scoring did not show significant differences among treatment groups, SHG/TPEF imaging analysis showed lower perisinusoidal collagen metrics (%PS: 0.27%-0.30% vs. 0.40% in MASH controls, p < 0.05). Furthermore, Efsubaglutide Alfa reduced serum ALT and AST levels and improved fasting glucose and triglycerides; fasting insulin was lower in semaglutide and high-dose Efsubaglutide Alfa groups, consistent with improved glycaemic control. CONCLUSIONS: Efsubaglutide Alfa reduced liver steatosis and improved SHG/TPEF-derived perisinusoidal collagen features, which supported further evaluation of Efsubaglutide Alfa for MASH, particularly for steatosis improvement and suggests potential effects on fibrosis-related features that warrant confirmation in longer duration studies.