Multicellular liver organoids for modeling fibrogenesis in metabolic dysfunction-associated steatohepatitis: Biological insights, current limitations, and translational perspectives

Metabolic dysfunction-associated steatohepatitis (MASH) progresses through coordinated interactions among injured hepatocytes, macrophages, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells, yet conventional in vitro models capture only part of this multicellular process.This review examines multicellular liver organoids developed to model MASH-associated fibrogenesis, with emphasis on platform design, disease-relevant phenotypes, mechanistic applications, and translational use.Current systems can reproduce selected features of disease progression, including steatosis, inflammatory amplification, HSC activation, and matrix-associated responses.Their performance, however, varies markedly with cell source, cellular composition, injury paradigm, culture duration, and analytical readouts, and not all models represent the same stage or aspect of MASH.Recent studies also show that these platforms can support investigation of fibrogenic cell-cell crosstalk and proof-of-concept therapeutic testing.Major limitations remain, particularly incomplete adult-like cellular maturation and tissue architecture, limited modeling of sustained fibrosis, and insufficient benchmarking against human disease.Multicellular liver organoids are therefore best viewed as complementary humanrelevant systems for mechanistic studies and stage-specific preclinical evaluation rather than complete surrogates of advanced MASH fibrosis.