Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD ‘human proximity score’ to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.

代谢功能障碍相关的脂肪肝病（MASLD），以前称为非酒精性脂肪肝病，包括脂肪变性和代谢功能障碍相关的脂肪性肝炎（MASH），导致肝硬化和肝细胞癌。临床前MASLD研究主要在啮齿类动物中进行；然而，最能概括人类疾病的模型尚未确定。我们对小鼠模型（主要是雄性）进行了广泛的回顾性审查（代谢表型、肝脏组织病理学、以人类为基准的转录组），并使用无偏见的 MASLD“人类接近度评分”对它们进行排名，以定义它们的代谢相关性和诱导 MASH 的能力纤维化。在这里，我们表明西方饮食与人类 MASH 密切相关；高胆固醇含量、延长研究时间和/或对促进疾病的途径进行基因操作是加剧肝损伤并加速显着（F2+）纤维化发展的必要条件。胆碱缺乏模型迅速诱导 MASH 纤维化，同时表现出相对较差的可转化性。我们根据常用 MASLD 模型与人类 MASLD 的接近程度进行排名，有助于选择合适的体内模型以加速临床前研究。