Integrative Multi-Omics of Cardiac Fibrosis: From Signaling Networks to Therapeutic Targets

Background: Cardiac fibrosis is a hallmark of virtually all forms of heart disease and a major determinant of ventricular stiffness, arrhythmogenicity, and heart failure progression. Despite its clinical relevance, effective antifibrotic therapies remain elusive due to the complex, cell-specific, and dynamic nature of fibrotic remodeling. Recent advances in omics technologies have enabled unprecedented resolution of the signaling pathways, epigenetic mechanisms, and cellular heterogeneity underlying fibrosis. A systems-level understanding of how fibroblast activation, immune infiltration, and extracellular matrix (ECM) remodeling are orchestrated in cardiac tissue is essential for identifying precise and actionable therapeutic targets. Methods and Results: This study applied an integrative multi-omics approach combining single-cell RNA sequencing, ATAC-seq, proteomics, and spatial transcriptomics in murine and human models of pressure overload–induced cardiac fibrosis. We identified discrete fibroblast subpopulations with distinct transcriptomic signatures, chromatin accessibility profiles, and functional states, including ECM-producing myofibroblasts, inflammatory fibroblasts, and matrix-degrading phenotypes. Network analysis revealed that TGF-β, IL-11, and Hippo signaling pathways act as central hubs coordinating the fibrotic program. Chromatin accessibility data demonstrated locus-specific enhancer activation at collagen and matricellular protein genes, while proteomics uncovered a secretory fingerprint of fibrotic progression. Pharmacologic targeting of upstream regulatory nodes using BET bromodomain inhibitors and YAP/TAZ pathway blockers significantly reduced fibrosis burden and improved diastolic performance in vivo. Conclusion: This integrative study maps the molecular and cellular architecture of cardiac fibrosis with high spatiotemporal resolution and identifies core regulatory circuits amenable to therapeutic modulation. By linking transcriptional and epigenomic states with functional outputs, we provide a blueprint for next-generation antifibrotic strategies that transcend nonspecific suppression and instead target disease-driving cell states and pathways.