Predicting metabolic dysfunction–associated steatotic liver disease risk using patient-derived induced pluripotent stem cells

Metabolic dysfunction-associated steatotic liver disease (MASLD) is reversible at early stages, making early identification critical. We previously demonstrated that patient-derived induced pluripotent stem cells (iPSCs) carrying MASLD-associated genetic risk variants exhibit greater oleate-induced intracellular lipid accumulation than those without these variants. This study aimed to develop an iPSC-based MASLD risk predictor using functional lipid accumulation assessments. We quantified oleate-induced lipid accumulation in iPSCs from three cohorts: (1) CIRM (22 cases, 20 controls), (2) POST (18 cases, 16 controls), and (3) UCSF (4 cases, 8 controls). Data from the CIRM cohort was used to define an iPSC-based MASLD risk score, which was subsequently validated in the POST and UCSF cohorts. Lipid accumulation was consistently higher in MASLD iPSCs across cohorts. The risk score achieved 44% sensitivity/75% specificity in POST and 75%/100% in UCSF. These findings suggest that oleate-induced lipid accumulation in iPSCs may be a predictor of MASLD risk. Larger studies incorporating additional cellular phenotypes, clinical, and genetic data could enhance predictive accuracy for MASLD surveillance and prevention.