What question did this study set out to answer?

The aim was to create a mouse model that mimics the progression of MASH-related hepatocellular carcinoma (HCC).

May 17, 2026Open Access

A Mouse in vivo Model Mimicking MASH-Related HCC Pathogenesis

Key Points

The aim was to create a mouse model that mimics the progression of MASH-related hepatocellular carcinoma (HCC).
Developed a murine model using a choline-deficient high-fat diet combined with hydrodynamic transfection of NRAS G12V/AKT oncogenes.
Evaluated disease progression through histopathological examination and liver transcriptomic analysis.
Compared the animal model's transcriptomic profile to that of human MASH-related HCC.
The model showed accelerated progression from steatohepatitis to HCC, with malignant lesions seen by study's end.
Transcriptomic analysis revealed significant molecular similarities between the model and human MASH-related HCC.
Key pathway dysregulations included those related to lipid metabolism, extracellular matrix remodeling, and oncogenic signaling.

Abstract

Background/Objectives: Hepatocellular carcinoma (HCC) derived from metabolic dysfunction-associated steatotic liver disease (MASH) has garnered increasing attention. To develop improved treatment strategies, it is crucial to comprehend its pathological processes. However, existing models frequently neglect to integrate key molecular features of human MASH-related HCC or require excessively prolonged experimental timelines. Our objective was to establish a novel murine model that facilitates accelerated and accurate progression by combining chronic metabolic stress with specific oncogenic drivers. Methods: A murine model was developed by subjecting mice to a choline-deficient, high-fat diet (CDAA-HFD) in conjunction with hydrodynamic transfection of NRAS G12V /AKT oncogenes. Disease progression was evaluated through histopathological analysis, while molecular fidelity was assessed by comparing the liver transcriptomic profile of the model to that of human MASH-related HCC. Results: Results: Histological examination demonstrated that the combination of CDAA-HFD and NRASG12V/AKT expedited the transition from steatohepatitis to hepatocellular carcinoma (HCC), with malignant lesions apparent at the conclusion of the study. Notably, comparative transcriptomic analysis indicated a significant molecular concordance between the animal model and human MASH-related HCC. Dysregulation was prominently observed in pathways regulating lipid metabolism (PPAR signaling, fatty acid metabolism), extracellular matrix remodeling (focal adhesion), and oncogenic signaling (PI3K-Akt pathway). Conclusion: Conclusions: Our integrated dietary and genetic model accurately replicates the essential pathological and molecular characteristics of human MASH-related HCC. This high level of fidelity confirms its value as a reliable preclinical platform for exploring disease mechanisms and assessing therapeutic strategies for this increasingly prevalent malignancy. Keywords: MASH-related HCC, mouse model, CDAA-HFD, hydrodynamic transfection, NRAS/AKT oncogenes

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