A Single‐Cell Proteomic Atlas of Cardiac Fibrosis Reveals Cell‐Type–Specific Remodeling and Discordant Protein Regulation

Cardiac fibrosis is a hallmark of progressive cardiac remodeling and heart failure, characterized by excessive extracellular matrix (ECM) deposition and complex cellular interactions. While bulk proteomic studies have provided insights into global protein alterations associated with fibrosis, they inherently average signals across heterogeneous cardiac cell populations, limiting resolution of cell-type-specific protein regulation. In this study, we applied single-cell proteomics by mass spectrometry (SCoPE2) to generate a proteomic atlas of cardiac fibrosis in an isoproterenol-induced mouse model. Across 1,163 high-quality single cells (ISO: 581; Control: 582), we quantified 4,251 proteins and resolved five major cardiac cell populations, including cardiomyocytes, endothelial cells, fibroblasts, M2 macrophage-like cells, and smooth muscle cells. Single-cell analysis revealed extensive cell-type-specific and discordant protein regulation that was largely masked in bulk proteomic measurements. These fundings demonstrate the utility of single-cell proteomics for resolving cellular heterogeneity in fibrotic cardiac tissue and provide a resource for future integrative studies of cardiac remodeling.