A novel human 3D steatohepatitis model recapitulating disease progression for evaluating the efficacy and mechanism of action of MASH therapeutics

Abstract

Fatty liver disease prevalence is rising in Japan due to Westernized diets. Despite extensive efforts, treatments for metabolic dysfunction-associated steatohepatitis (MASH), which carries high cirrhosis risks, remain unapproved in Japan. A primary cause of clinical failure is the inability of animal models to accurately predict human responses. We developed the “Functional Cellular Device (FCD^®)” to replicate human organ functions using 3D tissue engineering. Its first application, the “Human 3D Mini-Liver” (launched in 2023), consists of primary human hepatocytes and stellate cells. We successfully induced fibrosis in this model, observing neutral lipid accumulation and progressive fiber deposition. Transcriptomic analysis revealed an upregulation of oxidative stress and inflammation genes, followed by markers of stellate cell activation, demonstrating high pathophysiological similarity to human MASH. To validate its utility, clinical-stage MASH drugs were added to the fibrotic 3D mini-liver for 1-2 weeks. We evaluated stellate cell activation, collagen production, and fiber deposition. Integrating these phenotypic data with transcriptomic analysis enables precise efficacy prediction and mechanism of action (MOA) verification for drug candidates. Utilizing both healthy and diseased Human 3D Mini-Livers as evaluation tools facilitates drug safety and efficacy assessments based on human biology, significantly contributing to enhanced pharmaceutical R&D efficiency.