DSG2 (desmoglein 2) is a transmembrane cadherin component of desmosomal cell-cell junctions that functions primarily in cellular adhesion and tissue integrity. As a structural protein, DSG2 mediates the interaction between plaque proteins and intermediate filaments at the plasma membrane and within desmosomes, thereby promoting positive regulation of cell adhesion 1. Beyond its adhesive roles, DSG2 regulates pluripotency and stem cell function by sequestering β-catenin (CTNNB1) at cell-cell contacts, preventing its nuclear translocation and subsequent transcriptional activation 1. In cardiac tissue, DSG2 maintains desmosome junction formation at intercalated disks, supporting cardiac conduction and heart chamber integrity 2. Pathogenic DSG2 variants are the second most common cause of arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of cases and manifesting as left ventricular involvement with high heart failure risk 2. DSG2 mutations cause desmosome dysfunction, cardiomyocyte necrosis, immune infiltration, and fibrofatty replacement, with additional contributions from dysregulated inflammation and transforming growth factor-beta signaling 2. Notably, multiple DSG2 variants confer earlier disease onset, increased penetrance, and worse outcomes including end-stage heart failure and malignant ventricular arrhythmias compared with single-variant carriers 3. Beyond cardiac disease, DSG2 is implicated in Alzheimer's disease risk and promotes gemcitabine resistance in lung adenocarcinoma 14.