Animal models of lean metabolic dysfunction-associated steatotic liver disease (MASLD): bridging pathogenesis and...

Lean metabolic dysfunction - associated steatotic liver disease (MASLD) occurs in individuals with normal BMI and is linked to progressive liver injury, fibrosis, hepatocellular carcinoma, and adverse metabolic outcomes. Its distinct clinical and biological features underscore the need for tailored diagnostic and therapeutic strategies.

Herein, the authors review the dietary, genetic, and bile acid - focused animal models that recapitulate lean MASLD mechanisms. Literature was identified in PubMed and Scopus (January 2000-June 2025) using the terms lean MASLD, non-obese MASLD, MASH, and animal models, with reference lists screened for additional studies. Utilization of Methionine - choline-deficient (MCD) and choline-deficient (CD) diets can help reveal mechanisms pertinent to oxidative stress, macrophage activation, and fibrogenesis, whereas cholesterol- and bile acid - enriched diets more closely reproduce the steatohepatitis and fibrosis observed in lean human contexts. Genetic models (e.g. Pemt^-/^-, cGas^-/^-) reveal roles for autophagy, microbial DNA sensing, and metabolic rewiring. These platforms have been used to test candidate therapies, including GLP-1 analogues (exendin-4, liraglutide), kinsenoside, silibinin, and bile-acid modulators, and to interrogate gut - liver axis disruption that supports microbiota-targeted strategies.

Lean MASLD is mechanistically distinct from obesity-related MASLD. Animal models have advanced our understanding of their unique drivers, including bile acid dysregulation, leptin signaling, and oxidative stress. These insights may guide the development of targeted therapies tailored to lean patients and improve clinical outcomes through individualized approaches.