<p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.</p>