Organoid Models of Liver Fibrosis: Bridging Genetic and Epigenetic Mechanisms with Biomarker Discovery

ABSTRACT: Fibrosis is a pathological process characterized by excessive deposition of extracellular matrix, progressive tissue stiffening, and ultimately organ dysfunction. It represents a common endpoint of chronic injury in multiple organs, including the liver, lung, kidney, and heart, and contributes substantially to global morbidity and mortality. Increasing evidence indicates that genetic susceptibility and dynamic epigenetic regulation play important roles in determining individual responses to chronic injury and in shaping fibrogenic signaling pathways. Despite its clinical significance, effective therapies remain limited, partly due to an incomplete understanding of the complex cellular interactions and molecular mechanisms that drive fibrotic disease. Traditional experimental models, including two-dimensional cell cultures and animal systems, often fail to fully recapitulate human tissue architecture and disease complexity. Organoid technology has emerged as a promising platform for modeling human diseases in vitro. Organoids are three-dimensional multicellular structures derived from stem cells or primary tissues that self-organize to mimic key structural and functional aspects of native organs while preserving important genetic and epigenetic characteristics of the originating tissue. Recent advances have enabled the development of organoid-based models that capture critical features of fibrosis, including epithelial injury, fibroblast activation, and extracellular matrix remodeling. These systems provide powerful experimental platforms for investigating molecular mechanisms of fibrosis, studying the influence of genetic and epigenetic regulatory networks, and identifying candidate biomarkers associated with disease progression. This review summarizes current progress in the use of organoid systems to study fibrosis across different organs. The advantages and limitations of these models are discussed, and emerging technologies that may enhance their physiological relevance and utility for biomarker discovery and anti-fibrotic drug development are highlighted.