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Background and aims: Developing models that pertinently reflect immune system contributions to liver disease is essential for evaluating therapeutic candidates targeting inflammation, fibrogenesis and metabolic dysfunction. We aimed to characterize two rapid induction strategies in humanized immune system NCG mice (HISNCG) to generate distinct phenotypes of liver injury, advanced fibrosis and metabolic dysfunction-associated steatohepatitis (MASH).

Method: HIS-NCG mice engrafted with human CD34+ hematopoietic stem cells were subjected either to repeated carbon tetrachloride (CCl4) exposure over 23 days or to a 14-day high-fat diet deficient in methionine and choline (HF-MCD). Clinical condition, circulating alanine aminotransferase, liver histopathology, fibrosis stage, steatosis, human CD68+ macrophage infiltration and circulating galectin3-binding protein (LGALS3BP) were assessed to define the resulting phenotypes.

Results: Both injury paradigms caused rapid health deterioration and marked biochemical evidence of hepatic damage. CCl4 consistently produced advanced fibrosis, with most animals developing extensive bridging fibrosis or cirrhotic architecture in the absence of steatosis or human macrophage infiltration. In contrast, the HF-MCD diet induced the signature multi-component phenotype of MASH, including pronounced steatosis, a NAFLD Activity Score (NAS) of 6, low-grade fibrosis and substantial infiltration of human CD68+ macrophages. Elevated LGALS3BP further supported immunemediated inflammation and fibrogenesis.

Conclusion: These two humanized immune system mouse models provide complementary tools for the preclinical investigation of therapies targeting immune-driven pathways in liver disease. The CCl4 model recapitulates advanced fibrotic architecture, whereas the HF-MCD diet encompasses metabolic stress and human immune activation. In addition, a dual-humanized configuration integrating both human immune system and hepatocytes is also available. This expanded platform enables the evaluation of combination strategies relevant to both MASH and infectious hepatitis.