Primary Human Tissue Models for Metabolic Dysfunction‐Associated Liver Disease ‐ toward Streamlining Drug Discovery with Patient‐Derived Assays

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) are prevalent chronic liver diseases that are closely linked to metabolic syndrome, type 2 diabetes, and cardiovascular complications. Despite their rising incidence and growing socioeconomic burden, effective therapies remain limited. Traditional preclinical models often fail to replicate the complexity of human MASLD, particularly in capturing the interplay between patient-specific predisposition, metabolic dysfunction, immune activation and progressive fibrosis. In this review, a comprehensive overview of emerging human-based in vitro and ex vivo platforms is provided for use in MASLD research, including conventional 2D cultures, organoids, 3D spheroids, precision-cut liver slices, microphysiological systems, and bioprinted constructs. Their utility is evaluated for modeling different stages of MASLD and MASH and their alignment with key disease hallmarks is discussed. Furthermore, the different models are assessed for their capability to model pathophysiologically relevant nutritional exposure, to emulate genetic risk factors, to reflect the complex hepatic cell repertoire and to conduct high-throughput drug screenings. Recent successful applications of MASLD and MASH models are highlighted in drug discovery and development. Together, these insights aim to guide the refinement of human MASLD models to narrow the translational gap in MASH drug development.