Overexpression of Wild-Type HRAS Drives NASH to HCC Progression in Mouse Model

Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is 23 an aggressive and fatal disease with increasing incidence worldwide and poor therapeutic 24 outcomes.The etiology and pathological progression of non-alcoholic steatohepatitis (NASH) 25 -related HCC is multifactorial and multistage.However, no single animal model can accurately 26 mimic the full NASH-related HCC pathological progression and poses challenges in the 27 transition and other mechanism studies.Herein, a novel conditional inducible wild-type human 28 HRAS overexpressed mouse model (HRAS-HCC mouse) was established with 100 % 29 morbidity and death rate in about one month under normal diet and lifestyle.Advanced HCC 30 symptoms like ascites, thrombus, internal hemorrhage, jaundice, lung metastasis was first 31 mimicked in mouse.In-depth pathological features of NASH-related HCC were demonstrated 32 by pathological staining, biochemical tests and typical marker gene detections.Murine anti-33 PD-1 and sorafenib combined treatment effectively prolonged mice survival, which further 34 confirmed the accuracy and reliability of this model.We speculated that overexpression of 35 HRAS may initiate THBS1-COL4A3 axis to induce NASH with severe fibrosis and further 36 developed into HCC based on Protein-protein interaction (PPI) network and RNA sequencing 37 analysis.Collectively, our study firstly duplicates the natural sequential progressions in one 38 single murine model in very short period, providing an accuracy and reliable preclinical tool 39 for therapeutics evaluation for NASH to HCC.40 41