Single-nucleus transcriptomics reveals cardiomyocyte injury and fibro-inflammatory remodeling in early PKP2-deficient ARVC

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy caused primarily by mutations in desmosomal genes, among which pathogenic PKP2 variants being the most common genetic cause. Previous studies on ARVC have mainly focus on its middle and late pathological stages, whereas the early cellular and molecular events triggered by PKP2 loss remain poorly defined. We generated a cardiomyocyte-specific Pkp2 knockout mouse line and performed single-nucleus RNA sequencing (snRNA-seq) to delineate the early cellular landscape of ARVC. PKP2 loss triggered pathological remodeling of cardiomyocytes and induced a large-scale phenotypic shift in cardiac fibroblasts from a homeostatic state to an activated, matrix-producing population. Concomitantly, proangiogenic endothelial subsets expanded and Ccr2+/Spp1+ proinflammatory macrophages accumulated, reshaping the cardiac microenvironment. Cell-cell communication network analysis demonstrated enhanced intercellular crosstalk at the early stage of ARVC, with aberrant activation of profibrotic and inflammatory signaling pathways. By integrating transcriptomic analysis, immunofluorescence staining and ligand-receptor interaction analysis, we identified CCN2 may serve as a potential mediator in early-stage PKP2-related ARVC. Our study proposes a multicellular relay model of early ARVC pathogenesis and identifies CCN2 as a putative intercellular communication factor in PKP2-deficient hearts. These findings highlight intercellular communication networks as critical mediators of disease progression and potential therapeutic targets.