Integrating CRISPR genome editing with liver organoid and hiPSC-derived microfluidic platforms to model metabolic dysfunction–associated steatotic liver disease

Metabolic dysfunction–associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction–associated steatohepatitis (MASH), arise from the interplay of genetic susceptibility, metabolic stress, and multicellular hepatic dysfunction. However, causal interpretation of identified risk and protective variants remains constrained by the lack of human-relevant model systems. This review examines how dissecting the pathophysiological roles of MASLD-associated variants can refine our understanding of disease mechanisms and inform in vitro modeling strategies. It focuses on how human hepatic systems derived from induced pluripotent stem cells (hiPSCs), integrated with advances in Interspaced CRISPR-based genome editing, can aid our understanding of enabling precise genetic manipulation and the generation of isogenic, Human Leukocyte Antigen (HLA) -matched models for liver research. Lastly, by combining these approaches with liver differentiation protocols, organoid systems, and liver-on-chip platforms, a robust framework emerges for modeling patient-specific genetic variation. This integrated strategy will support mechanistic studies, therapeutic target validation, and the evaluation of safety and efficacy for genome-editing interventions in MASLD. • CRISPR-edited hiPSC liver models allow isogenic study of MASLD/MASH risk variants. • Liver organoids and microphysiological systems recreate multicellular tissue crosstalk. • Genome editing + liver-on-chip bridges gaps between in vitro models and human disease. • LoCs and organoids speed translation in drug development and clinical research.