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

Jessica L Maiers, Tiebing Liang, Tingbo Guo, Sha Cao, Prakash Ramachandran, Teresa J Raba, Stefano Romeo, Oveis Jamialahmadi, Arman Shahrisa Etu, Naga Chalasani

Journal: Hepatology communications 2026;10(10):

PMID: 42748406

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Abstract

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.

Address: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.; Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.; Department of Medicine (H7), Center for Molecular Medicine (CeRM), Karolinska Institutet, Huddinge, Stockholm, Sweden.; Department of Endocrinology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.; Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.; Department of Medicine (H7), Center for Molecular Medicine (CeRM), Karolinska Institutet, Huddinge, Stockholm, Sweden.; Translational Research for Diabetes UMR 1190, University of Lille, Lille, France.

DOI: 10.1097/HC9.0000000000000991

MeSH Terms: Humans, Liver Cirrhosis, Disease Progression, Transcriptome, Liver, Single-Cell Gene Expression Analysis, Gene Expression Profiling