Cross-organ single-cell integration identifies liver-specific fibroblast programs and HGF-MET/AGT-AGTR1B axes that link fibrosis to hepatocarcinogenesis.

BACKGROUND: Fibrosis is a pan-organ wound-healing program, yet stromal mechanisms that are liver-selective and connect liver fibrosis to hepatocellular carcinoma (HCC) remain incompletely defined. METHODS: We assembled public single-cell RNA-seq datasets from fibrotic heart, kidney, liver, and lung with matched controls and applied a unified Seurat integration workflow, differential expression and pathway enrichment, Slingshot pseudotime, and CellChat ligand-receptor inference. We used cross-organ subtraction of shared pan-fibrotic signatures to nominate liver-enriched fibroblast (FB) genes and pathways, intersected these candidates with HCC single-cell datasets and FB trajectories to prioritize fibrosis-aligned, tumor-progression genes, and compared intercellular communication across organs focusing on hepatocyte-FB pairs. RESULTS: Integration recovered robust FB clusters in each organ without dominant batch effects, supported by canonical FB markers (PDGFRA, LAMB1). Liver FB programs showed endocrine-metabolic rewiring (e.g., insulin/glucagon/FOXO signaling) alongside suppression of xenobiotic/GPCR modules. In HCC, FB subclustering resolved healthy and pathogenic FB states, and Slingshot captured a continuous healthy-to-pathogenic activation axis. Differential expression identified 126 liver-specific upregulated and 239 downregulated DEGs; overlap with HCC pseudotime highlighted SULF2/TIMP3 (fibrosis , progression ) and TNFAIP8 (fibrosis , progression ). Cross-organ CellChat comparisons further prioritized HGF-MET and AGT-AGTR1B as liver-selective axes relative to heart, kidney, and lung, with stellate-to-hepatocyte (HGF-MET) and hepatocyte-to-stellate (AGT-AGTR1B) ligand-receptor expression correlations observed in liver fibrosis and replicated in independent HCC datasets. CONCLUSIONS: Cross-organ single-cell integration prioritizes liver-selective stromal circuitry and nominates hepatocyte-FB axes (HGF-MET, AGT-AGTR1B) as plausible links between fibrogenic remodeling and a pro-tumorigenic niche, yielding testable hypotheses at the interface of regeneration, RAS biology, and tumor initiation.