Decoding Liver Fibrosis: How Omics Technologies and Innovative Modeling Can Guide Precision Medicine

Abstract

The burden of chronic liver disease (CLD) is dramatically increasing. It is estimated that 20-30% of the population worldwide is affected by CLD. Hepatic fibrosis is a symptom common to all CLDs. Although it affects liver functional activities, it is a reversible stage if diagnosed at an early stage, but no resolutive therapy to contrast liver fibrosis is currently available. Therefore, efforts are needed to study the molecular insights of the disease. Emerging cutting-edge fields in cellular and molecular biology are introducing innovative strategies. Spatial and single-cell resolution approaches are paving the way for a more detailed understanding of the mechanisms underlying liver fibrosis. Cellular models have been generated to recapitulate the in-a-dish pathophysiology of liver fibrosis, yielding remarkable results that not only uncover the underlying molecular mechanisms but also serve as patient-specific avatars for precision medicine. Induced pluripotent stem cells (iPSC) and organoids are incredible tools to reshape the modeling of liver diseases, describe their architecture, and study the residents of hepatic tissue and their heterogeneous population. The present work aims to give an overview of innovative omics technologies revolutionizing liver fibrosis research and the current tools to model this disease.

Keywords: PLCS; iPSC-derived liver cells; liver fibrosis; organoids; personalized medicine; single-cell RNA-sequencing; spatial transcriptomics.

Figure 1

Strategies to study liver fibrosis. Liver fibrosis is a common outcome to many etiologies. Cell heterogeneity can be investigated by single-cell RNA-sequencing (scRNA-seq), while spatial architecture can be studied by spatial transcriptomics (ST). From the homogenized tissue, a single-cell suspension is barcoded, and RNA is captured to generate cDNA and DNA libraries. The libraries are deep sequenced to decode single-cell transcripts and population heterogeneity. The samples for ST are laid out on the grid of a glass covered with polydT barcode probes, the transcripts are then released, and cDNA libraries are constructed and sequenced to create a spatially resolved map. Created in BioRender. Codotto, G. (2025) https://BioRender.com/l60i579.

Figure 2

Scheme of in vitro and ex vivo available models to investigate liver fibrosis. The 2D models include immortalized cell lines, induced pluripotent stem cells (iPSC)-derived hepatic cells, and primary hepatic cell lines, while the 3D models include immortalized cell-derived spheroids, multi-lineage organoids, and precision-cut liver slices (PLCS). Created in BioRender. Codotto, G. (2025) https://BioRender.com/l60i579.