Impact of Spheroid Use for Identifying Hepatocellular Carcinoma Features: Involvement of Kinase-Mediated Molecular Pathways

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, owing to its molecular complexity and limited therapeutic options. Three-dimensional (3D) <i>in vitro</i> models more accurately recapitulate <i>in vivo</i> conditions than traditional two-dimensional (2D) models, due to their ability to accurately reproduce the tumor microenvironment (TME). Among these models, HepG2 cell-derived spheroids have become an important tool for drug screening, toxicity assessment, and liver cancer research. This review highlights the advantages and limitations of currently available 3D culture systems. In particular, special attention is given to the multifaceted role of leucine-rich repeat kinase 2 (<i>LRRK2</i>), a gene traditionally associated with neurological disorders but increasingly implicated in cancer, a kinase, which emerges as a promising therapeutic target in HCC since it regulates oxidative stress, lipid metabolism, and treatment responses, all of which contribute to tumor progression. Finally, we explore future directions, including organ-on-chip technologies and co-culture systems, which hold considerable promise for improving precision medicine and translational research in HCC.