Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 15 1 2025 04 15 A Novel GLP-1 and FGF21 Fusion Protein for the Treatment of Non-alcoholic Steatohepatitis (NASH) 162 175 10.34172/apb.43672 EN Zhipeng Zhang https://orcid.org/0009-0005-4922-7630 Yanqin Ma Cheng Xie Yan He Dong Wang Huaien Song Miao Yuan Xiaomei Zhang https://orcid.org/0000-0001-8494-9245 Journal Article 10.34172/apb.43672 2024 08 20 2024 12 03 Purpose: The objective of this study was to develop and produce a novel fusion protein that combines GLP-1 (glucagon-like peptide-1) and FGF21 (fibroblast growth factor 21), with the aim of achieving synergistic pharmacological effects through the targeting of dual pathways, followed by validation of these effects in a non-alcoholic steatohepatitis (NASH) model. Methods: We utilized C57Bl/6J mice to establish a high-fat diet (HFD)/CCl4 NASH model, with the aim of assessing the drug efficacy across low, medium, and high (0.3, 1, 3 mpk) dose groups administered twice a week for 28 days. Results: The animal pharmacological experiment of HSP763-01 demonstrated a significant reduction in body weight without apparent appetite suppression. Analysis of blood biochemical indicators revealed a marked decrease in triglycerides (TG), serum total cholesterol (TCHO or TC), low-density lipoprotein (LDL), and blood sugar levels with a significant dose-dependent effect. Additionally, Liver tissue analysis indicated notable alleviation of liver fatty degeneration and ballooning degeneration, as well as partial relief of lobular inflammation with a significant dose-dependent effect. However, due to the severe liver fibrosis induced by tetrachloromethane (CCl4 ) in mice (3rd grade), HSP763-01 exhibited limited efficacy in alleviating fibrosis. Conclusion: HSP763-01 exhibited a clear dual target of GLP-1 and FGF21, which has been demonstrated by a robust response to the HFD/CCl4 model, showing a marked improvement in lipid metabolism, lowering of blood glucose, weight loss, significant alleviation of liver steatosis, ballooning, and partial relief of lobular inflammation and fibrosis.