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The advanced technologies using 3D co\u2010culture methods enabled researchers to develop cell\u2013cell and cell\u2013extracellular matrix (ECM) interactions similar to the natural liver, resulting in the improvement of the metabolic performance of ex\u00a0vivo cultured primary hepatocytes (PHs). Although PHs are the best candidates in cell\u2010based drug screening methods, access to these cells is limited. The application of stem cell\u2013derived hepatocyte\u2010like cells (HLCs) could overcome these limitations in high\u2010throughput assessments. However, the functional capacity of HLCs is not enough. Hepatoma cells could be reliable substitutes for PHs and HLCs; however, compared to PHs, their metabolic performance is low. Mimicking the complexity of the liver microenvironment using hepatoma cells and liver\u2010specific stromal cells in a 3D culture condition represents an innovative, accessible, and scalable platform to accelerate drug development if the metabolic capacity of hepatoma cells is enhanced. This can reduce time, costs, and address the ethical concerns related to animal models and pluripotent stem cells. 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