DSP (desmoplakin) is a critical structural protein that functions as a key component of desmosomes, specialized cell-cell adhesion junctions essential for tissue integrity 1. The protein plays fundamental roles in cellular adhesion by anchoring keratin filaments at desmosome junctions and organizing the intermediate filament network within cells. DSP is particularly important in cardiac tissue, where pathogenic variants cause arrhythmogenic cardiomyopathy and dilated cardiomyopathy 12. Clinical studies demonstrate that DSP variants contribute to approximately 2.4% of dilated cardiomyopathy cases, with nonmissense DSP variants showing significantly higher risk for life-threatening arrhythmic events (hazard ratio 2.3) and end-stage heart failure (hazard ratio 5.0) compared to other desmosomal gene variants 2. Beyond cardiac function, DSP expression in adipose tissue correlates with cardiometabolic health markers, with higher expression in visceral compared to subcutaneous fat associated with blood pressure and insulin resistance 3. The gene also shows tissue-specific expression patterns linked to pulmonary fibrosis risk, where genetic variants affect both DSP expression and DNA methylation 4. These findings establish DSP as a multifunctional protein critical for maintaining structural integrity across multiple organ systems, with significant clinical implications for cardiovascular and metabolic diseases.