PKP2 (plakophilin 2) is a critical desmosomal protein essential for cardiac structural integrity and electrical function. As a component of desmosome cell-cell junctions, PKP2 maintains cellular adhesion and regulates localization of desmosomal proteins including DSC2, DSG2, and DSP 1. In cardiomyocytes, PKP2 is required for proper desmosome formation and electrical synchrony, facilitating sodium current propagation via ANK3 stabilization and SCN5A localization to intercalated disks [UniProt]. PKP2 also preserves nuclear envelope integrity and mitochondrial function through DES localization regulation, protecting against DNA damage and transcriptional dysregulation 2. PKP2 mutations cause arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common desmosomal cardiomyopathy 3. PKP2 variants are associated with increased risk of sudden cardiac death and major ventricular arrhythmias compared to other genetic cardiomyopathies 3. Genome-wide association studies identified PKP2 as an atrial fibrillation risk locus, highlighting its role in cardiac structural remodeling 45. Recent evidence demonstrates that AAV-mediated PKP2 restoration rescues desmosomal integrity, improves sodium conduction, normalizes contractility, and prevents cardiac dysfunction in preclinical models, supporting therapeutic potential for PKP2-related cardiomyopathy 6.