Mechanistic insights and translational perspectives on liver fibrosis through single-cell transcriptomics

Liver fibrosis is a defining feature of chronic liver diseases and can progress to cirrhosis and liver failure. Single-cell RNA sequencing (scRNA-seq) enables high-resolution analysis of cellular heterogeneity and multicellular interactions during fibrogenesis. In this narrative review, we analyzed published single-cell transcriptomic studies from experimental models and human cohorts, focusing on cell-type–specific programs, cell-state trajectories inferred by Monocle, and intercellular communication networks predicted using CellChat and CellPhoneDB. Hepatic stellate cells (HSCs) consistently emerged as the primary extracellular matrix–producing cells, with conserved activation signatures involving collagen synthesis, Phosphatidylinositol 3-kinase–Protein kinase B (PI3K–AKT) signaling, and matrix organization. Macrophage analyses identified fibrosis-associated subsets, including CD9 + and TREM2 + scar-associated macrophages (SAMs), which regulate inflammation, angiogenesis, and stromal remodeling. Liver sinusoidal endothelial cells undergo capillarization and transcriptional reprogramming linked to WNT signaling and antigen presentation. B cells exhibit activation signatures related to B-cell receptor signaling. Trajectory analyses infer potential cell-state transitions based on transcriptional similarity from quiescent to pathogenic states, including stepwise HSC activation and monocyte-to-macrophage differentiation. Cell–cell communication analysis highlights HSC–macrophage interactions, with key axes such as predicted Chemokine ligand 2–chemokine receptor 2 (CCL2–CCR2) and transforming growth factor-β–transforming growth factor-β receptor (TGFβ–TGFβR) signaling interactions that may contribute to fibrogenic communication networks. These findings define conserved multicellular programs and support integrated multi-omics approaches for biomarker discovery and therapy.