Advances in Liver Organoid Technology: A Paradigm Shift in Hepatic Research and Therapeutics

The liver is essential for maintaining metabolic functions, detoxification, and homeostasis. It is crucial to recognize any malfunction in patients with liver disease/failure. To better understand disease pathology, a combination of clinical investigation and emerging technologies, such as organoid models, provides powerful tools for advancing disease studies. There are limitations in animal models, and conventional twodimensional (2D) cultures have hindered accurate modeling of liver physiology and pathology. Liver organoids, three-dimensional, self-organizing structures produced using pluripotent or adult stem cells, have increased prominence as advanced in vitro systems that recapitulate the architecture, cellular heterogeneity, and functionality of native liver tissue. This review explores the formation and cellular sources of liver organoids, such as multi-type cell and single-type cell systems, and highlights the role of engineered extracellular matrices and bioactive signaling pathways in their formation. We further address the integration of advanced technologies, for example, CRISPR/Cas9, viral transduction, three-dimensional (3D) bioprinting, and a liver-on-achip platform, which have revolutionized the customization and application of liver organoids. Their utility in drug screening, modeling liver diseases, such as genetic, infectious, and fibrotic conditions, and also applications in regenerative medicine are discussed. Liver organoids depict a transformative tool for understanding liver tissue pathophysiology, screening therapeutics, advancing personalized medicine, and tissue engineering.