Engineered hepatic cells with stable expansion and heat-inducible liver function

Scalable production of functional hepatocytes remains a major challenge for the development of in vitro liver models. Hepatoma-derived cells are attractive due to their proliferative capacity, but their typically low liver-specific functions limit both clinical and industrial applications. Here, we describe a heat-inducible hepatic cell line (hi-Hep), generated by overexpressing BRCA1-associated protein-1 (BAP1) in the human hepatoma-derived cell line HepG2/8F_HS. A transient heat stimulus (43 °C, 30 min) induced growth arrest and markedly enhanced liver-specific functions, including albumin secretion, ammonia clearance, and cytochrome P450 activity, surpassing those of both HepG2 and HepG2/8F_HS. Exploratory transcriptomic profiling revealed coordinated upregulation of DNA replication and biosynthetic pathways, consistent with a shift toward a metabolically active hepatic phenotype. In three-dimensional culture, hi-Hep organoids embedded in alginate-collagen hydrogels exhibited further enhanced detoxification capacity. These findings suggest that BAP1 overexpression may contribute to the enhancement of hepatic metabolic and detoxification functions in hepatoma-derived cells, supporting the potential utility of hi-Hep as a platform for bioartificial liver systems and drug testing models.