Practical Guidance for Matching Preclinical Models to Therapeutic Mechanism in Liver diseases

Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from simple steatosis to steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma, spanning a broad pathological spectrum. No single animal model has yet fully reproduced this human disease because metabolic, inflammatory, fibrogenic, and genetic factors interact in complex, stage-specific ways throughout the process. Major experimental platforms for MASLD/MASH include dietary, genetic, chemically accelerated, and multifactorial animal models ; however, efficacy can be difficult to judge accurately when a candidate's mechanism of action does not match the induction mechanism of the model. Two recently approved MASH therapies further illustrate that interpretation of preclinical efficacy depends not only on model selection but also on whether the treatment duration is sufficient for the expected mechanism to impact the endpoint of interest. Accordingly, this review reorganizes MASLD/MASH animal models by induction mechanism, metabolic and hepatic phenotype, suitability for translational research, and model-specific confounders, to propose a rational model-selection framework that begins with the candidate's therapeutic mechanism. In conclusion, the mechanism-based model-selection framework and model-by-model comparisons presented here are expected to provide practical help to researchers developing and validating new MASH therapies, thereby offering a practical foundation for experimental reproducibility and clinical translation.