2505-P: Mazdutide, a GCGR/GLP-1R Dual Agonist, Alleviates MASH and Liver Fibrosis through Hepatocytes–Hepatic Stellate Cells Cross Talk

Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by liver steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Mazdutide, an agonist of glucagon-like protein-1 receptor (GLP-1R) and glucagon receptor (GCGR), has been demonstrated to alleviate MASH and liver fibrosis in animal models. However, its underlying mechanism and exact target cells in liver fibrosis remain unclear. Herein, we explored its effect on hepatocytes and the crosstalk between Hepatocytes and Hepatic Stellate Cells (HSCs) in vitro and in vivo. Methods: C57BL/6J mice were provided with a diet that was high in fat, fructose, and cholesterol(AMLN). After 32 weeks, the mice were randomly assigned to receive either vehicle or Mazdutide by subcutaneous injection every 2 days for 6 weeks. Immunohistochemistry and biochemical assays were conducted to evaluate the drug effects on inflammation and liver fibrosis. Liver samples were subjected to transcriptome analysis and single cell sequencing analysis. Hepatocytes were treated with palmitic acid and Mazdutide and their effect on HSCs was further explored via condition medium and coculture model. Results: Mazdutide alleviated liver fat accumulation, inflammation and liver fibrosis. It could reprogram hepatic cholesterol metabolism and homeostasis and stimulate complement and coagulation cascades activation through GCGR on Hepatocytes. Mazdutide decreased Hepatocytes lipid deposition and decrease cholesterol content, and thereby interrupting Hepatocytes-induced HSCs activation and reducing collagen secretion. Conclusion: Mazdutide alleviates liver fibrosis in MASH mice via regulating Hepatocytes lipid metabolism and inhibiting HSCs activation through indirect effect, which provides a novel therapeutic avenue for MASH and liver fibrosis. Disclosure L. Zhang: None. H. Wang: None. L. Li: None. H. Jiang: None. Funding National Natural Science Foundation of China (82020108029, 82073398, 823023677, 82473867, 82370424)