Comparative Analysis of Lipid Accumulation and Antioxidant Responses in MASLD and Control iPSC-Heps

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition characterized by lipid accumulation and associated inflammation, driven by genetic, environmental, and metabolic factors. Much is still unknown about the mechanisms of the disease, and research on this is important for advancing effective treatments. This study investigated lipid accumulation and oxidative stress responses to varying concentrations of oleic acid (OA) and palmitic acid (PA) in induced pluripotent stem cell-derived hepatocytes (iPSC-Heps) from MASLD and healthy donors. BODIPY staining revealed that MASLD iPSC-Heps exhibit significantly higher lipid accumulation than controls, especially under prolonged OA and PA exposure. Additionally, PLIN2 expression was consistently higher in MASLD cells, consistently with increased lipid accumulation. Further, gene expression analysis revealed that MASLD iPSC-Heps exhibited an impaired antioxidant response after fatty acid treatments, compared to the adaptive upregulation in the control cells. These findings emphasize MASLD cells’ increased vulnerability to lipid overload and oxidative stress, suggesting a link between lipid accumulation and cellular dysfunction. Experiments suggest that targeted interventions to enhance antioxidant pathways could mitigate disease progression. This research adds to understanding MASLD’s pathogenesis, offering insights for developing therapeutic approaches for MASLD and related liver disorders.