Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiomyopathy. The pathophysiological events are well understood, yet the underlying molecular mechanisms remain undefined. Here, we created a novel research platform comprising of patient originated hiPSC-derived cardiomyocytes bearing a pathological PKP2 mutation (PKP2 c.2013delC/WT), a novel knock-in murine model carrying the equivalent mutation (Pkp2 c.1755delA/WT), and human explanted ACM hearts, to identify disease driving mechanisms. Pkp2 c.1755delA/WT mice displayed reduced desmosomal and adherens junctions protein levels and protein disarray of the intercalated discs in areas of active fibrotic remodeling. These findings were validated in hiPSC-derived cardiomyocytes and human explanted ACM hearts. Led by proteomics data, we demonstrated that the ubiquitin-proteasome system was responsible for the observed desmosomal protein degradation. The research platform presented here provides a strong scientific basis to identify bona fide pathological processes and will aid in the development of potential therapies for the prevention of ACM disease progression.