Multiomics Analysis Reveals Extensive Remodeling of the Extracellular Matrix and Cellular Metabolism Due to Plakophilin-2 Knockdown in Guinea Pigs

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death (SCD) in young individuals, yet the mechanisms underlying its pathogenesis, particularly the role of plakophilin-2 (PKP2), remain incompletely understood. This study aimed to elucidate the profile of molecular and metabolic consequences of PKP2 knockdown in a guinea pig model of ARVC. We employed adeno-associated virus serotype 9 (AAV9) to deliver PKP2 shRNA, establishing a model that recapitulates key features of human ARVC, including right ventricular (RV) enlargement, sudden death, and cardiac lipid accumulation. Proteomic analysis revealed significant dysregulation of extracellular matrix (ECM) proteins, PI3K-Akt signaling, and energy metabolism in PKP2-deficient RVs. Metabolomic profiling further highlighted alterations in lipid metabolism and inter-metabolites of TCA cycle, with a notable shift towards fatty acid oxidation. These findings suggest that PKP2 deficiency triggers a cascade of molecular events leading to ECM remodeling, metabolic reconfiguration, and potential mitochondrial dysfunction, which may contribute to the development of ARVC. Our study provides novel insights into the early molecular mechanisms of ARVC and identifies potential therapeutic targets for this underexplored disease.