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Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet\u2010induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16\u00a0weeks. These findings reveal gut\u2010liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut\u2010pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic\u2010guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease\u2010associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.<\/jats:p>","DOI":"10.1002\/advs.202404326","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T02:00:25Z","timestamp":1719885625000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD"],"prefix":"10.1002","volume":"11","author":[{"given":"Zun Siong","family":"Low","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine Nanyang Technological University Singapore  Clinical Sciences Building, 11 Mandalay Road Singapore 308232 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