New approach methodologies to model liver fibrosis in metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant global health issue and a leading cause of liver fibrosis, with no effective pharmacological treatments available. Conventional 2D cell cultures and animal models do not fully recapitulate the complex cell-cell interactions and multicellular microenvironment that drive disease progression in humans, which limits their ability to predict therapeutic efficacy accurately. The recent introduction of the FDA Modernization Act 2.0 has paved the way for the use of human-relevant New Approach Methodologies (NAMs) in drug discovery and toxicity testing. This review focuses on recent advancements in NAMs that model MASH-associated liver fibrosis, such as human liver spheroids, iPSC-derived liver organoids, precision-cut liver slices, 3D bioprinting, and liver-on-a-chip systems. By mimicking multicellular interactions and the liver microenvironment, NAMs offer a valuable platform for mechanistic studies and drug screening. Assessing their strengths and limitations can lead to deeper mechanistic insights and expedite the development of new therapeutics for MASH-associated liver fibrosis. [BMB Reports 2026; 59(4): 219-226].