1640-P: Targeting Cathepsin L for Liver Fibrosis—Mechanistic Insights and Therapeutic Potential in a Diabetic Mouse Model

Introduction and Objective: Diabetes and non-alcoholic fatty liver disease (NAFLD) are closely linked, with type 2 diabetes markedly increasing the risk of NAFLD. Our prior research identified the lysosomal enzyme Cathepsin L (CTSL) as upregulated in diabetic patients, with high glucose levels activating CTSL function (PMID: 39150053). Notably, CTSL may cleave Collagen18A1 to generate endostatin, which activates hepatic stellate cells and accelerates fibrosis. Methods: We developed a novel CTSL inhibitor that specifically targets CTSL with minimal side effects. The role and mechanism of CTSL in liver fibrosis were investigated. Results: High glucose induced CTSL maturation in human hepatocellular carcinoma cells (Huh7). Conditioned media from glucose-treated Huh7 cells activated human hepatic stellate cells (LX-2), increasing the expression of Collagen I and αSMA. In a db/db diabetic mouse model of liver fibrosis, tissue structure and pathological changes were assessed using HE staining, fibrosis severity by Sirius red staining, and inflammation infiltration by F4/80 immunohistochemistry. Treatment with the CTSL inhibitor significantly improved liver histology, reducing fibrosis and inflammation. Conclusion: The CTSL inhibitor effectively alleviated fibrosis and inflammation in db/db diabetic mice, highlighting its potential as a therapeutic agent for NAFLD. Disclosure M. Li: None. M. Zhao: None. J. Yang: None. Funding National Natural Science Foundation of China (82341076)