A single-cell transcriptomic analysis of human liver cirrhosis reveals the fibrotic niche's cellular composition and interactions. The study profiles over 100,000 single cells from healthy and cirrhotic human livers, identifying novel cell populations, including TREM2+ CD9+ macrophages, ACKR1+ and PLVAP+ endothelial cells, and PDGFRα+ collagen-producing mesenchymal cells. These cells form a complex, pro-fibrogenic network involving key pathways such as TNFRSF12A, PDGFR, and NOTCH signaling. The fibrotic niche is characterized by the expansion of scar-associated macrophages, which display a pro-fibrogenic phenotype and are derived from circulating monocytes. These macrophages interact with endothelial cells and mesenchymal cells, promoting fibrosis through mechanisms involving collagen production, leucocyte transmigration, and angiogenesis. The study also identifies distinct endothelial subpopulations, including scar-associated endothelia, which are spatially restricted to fibrotic areas and contribute to fibrosis by enhancing leucocyte recruitment. The mesenchymal cells, including hepatic stellate cells and scar-associated mesenchymal cells, play a critical role in fibrogenesis. The research provides a comprehensive single-cell atlas of the fibrotic niche, highlighting the importance of specific ligand-receptor interactions and pathways in liver fibrosis. This work offers a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis and underscores the potential of single-cell transcriptomics in understanding the molecular basis of fibrotic diseases. The findings emphasize the need for targeted therapies that address the complex interactions within the fibrotic niche to effectively treat liver fibrosis.A single-cell transcriptomic analysis of human liver cirrhosis reveals the fibrotic niche's cellular composition and interactions. The study profiles over 100,000 single cells from healthy and cirrhotic human livers, identifying novel cell populations, including TREM2+ CD9+ macrophages, ACKR1+ and PLVAP+ endothelial cells, and PDGFRα+ collagen-producing mesenchymal cells. These cells form a complex, pro-fibrogenic network involving key pathways such as TNFRSF12A, PDGFR, and NOTCH signaling. The fibrotic niche is characterized by the expansion of scar-associated macrophages, which display a pro-fibrogenic phenotype and are derived from circulating monocytes. These macrophages interact with endothelial cells and mesenchymal cells, promoting fibrosis through mechanisms involving collagen production, leucocyte transmigration, and angiogenesis. The study also identifies distinct endothelial subpopulations, including scar-associated endothelia, which are spatially restricted to fibrotic areas and contribute to fibrosis by enhancing leucocyte recruitment. The mesenchymal cells, including hepatic stellate cells and scar-associated mesenchymal cells, play a critical role in fibrogenesis. The research provides a comprehensive single-cell atlas of the fibrotic niche, highlighting the importance of specific ligand-receptor interactions and pathways in liver fibrosis. This work offers a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis and underscores the potential of single-cell transcriptomics in understanding the molecular basis of fibrotic diseases. The findings emphasize the need for targeted therapies that address the complex interactions within the fibrotic niche to effectively treat liver fibrosis.