A Mouse in vivo Model Mimicking MASH-Related HCC Pathogenesis.

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.