Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses steatosis and steatohepatitis (NASH/MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASH 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” (MHPS) 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 selection of appropriate in vivo models to accelerate preclinical research.This study has been conducted as part of the Preclinical work package of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project. The LITMUS study is a large multi-centre study aiming to evaluate Non-Alcoholic Fatty Liver Disease biomarkers. The Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under Grant Agreement 777377, funded the LITMUS study. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. EMBL-EBI Core funding supported EP and IK through funding and computing resources from EMBL-EBI. Funding from the MRC (Medical Research Council) supported IK. M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06-miRNASH), the Foundation for Liver Research (Intramural Funding), Associazione Italiana Ricerca sul Cancro (IG2022 Grant n. 27521) and Ministry of University and Research on Next Generation EU Funds [COD: P202222FCC, CUP: H53D23009960001, D.D. MUR 1366 (01-09-2023), Title: “System Biology” approaches in HCV Patients with Residual Hepatic Steatosis after Viral Eradication; Cod PE00000003, CUP: H93C22000630001, DD MUR 1550, Title: “ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security – Working ON Foods”; Cod: CN00000041, CUP: H93C22000430007, Title PNRR “National Center for Gene Therapy and Drugs based on RNA Technology”, M4C2-Investment 1.4; Code: CN00000013, CUP: H93C22000450007, Title PNNR: “National Centre for HPC, Big Data and Quantum Computing”). A.V-P. is funded by MRC MDU, MRC Metabolic Diseases Unit (MC_UU_00014/5): Disease Model Core, Biochemistry Assay Lab, Histology Core and British Heart Foundation. F.O. is funded by UK Medical Research Council Program Grants MR/K0019494/1 and MR/R023026/1. C.M.P.R. is supported by Fundação para a Ciência e Tecnologia (PTDC/MED-FAR/3492/2021) and La Caixa Foundation (LCF/PR/HR21/52410028). Q.M.A. is supported by the Newcastle NIHR Biomedical Research Centre. S.L.F. and W.S. are supported by the NIH (NIH R01 DK128289; NCI 5P30CA196521-08 to S.L.F.; NIH R01 DK136016 to W.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript
