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