Conserved hepatic RNA signatures across multiple cohorts reveal novel mechanistic clues for advanced fibrosis in human MASLD.

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BACKGROUND: Fibrosis development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is a key indicator of disease progression and clinical outcome. Bulk and single-cell transcriptomics on human tissue have advanced understanding of fibrosis progression, but interstudy heterogeneity and limited sample size hinder the identification of consistent and targetable fibrogenic mechanisms. METHODS: To identify conserved fibrogenic mechanisms, we performed a comprehensive meta-analysis of hepatic transcriptomic data with fibrosis stage characterized from ~1000 patients with MASLD. RESULTS: Our meta-analysis revealed 846 differentially regulated genes associated with fibrosis progression (F3-4 vs. F0-1). Pathway analysis showed that these genes are involved in matrix organization (THBS2, ADAMTSL2), inflammation (CXCL6, CCL19), solute transport (SLC13A5, SLC16A10), and metabolism (AADAT, GRAMD1B). scRNA-seq-based deconvolution revealed increased proportions of immune (CD4+ T cells), endothelial (HA endo cells), and mesenchymal (myofibroblasts) cell types, and loss of LSECs in patients with advanced fibrosis in the meta-analysis. Finally, analysis of ligand-receptor pairs identified putative cell-matrix interactions (MMP7-CDH6), cell signaling (PDGFD-PDGFRA), and immune cell interactions (ANXA1-FPR1) associated with fibrosis conserved across multiple datasets and enriched in patients with fibrosis. CONCLUSIONS: We identified conserved transcriptomic changes and gene networks in patients with advanced fibrosis, as well as putative ligand-receptor interactions that facilitate cell-cell interactions that drive fibrosis. These findings will inform mechanistic studies and the development of anti-fibrotic therapies.