Arrhythmogenic cardiomyopathy (ACM) is an inherited disease mainly caused by desmosomal gene mutations and characterized by myocardial loss, replacement with fibro-fatty tissue, arrhythmias and sudden cardiac death. To date, it is unclear which cell type and molecular mechanisms contribute to the fibro-fatty phenotype. The epicardium is the outer mesothelial layer of the heart which has the capacity to undergo epithelial-to-mesenchymal transition (EMT) and differentiate into various cardiac cell types. The aim of this study is to investigate whether epicardial cells contribute to the excess fibro-fatty infiltration seen in ACM patients. To this end, we differentiated induced pluripotent stem cells (iPSCs) from an ACM patient with a haploinsufficiency-causing mutation in the desmosomal gene plakophilin-2 (PKP2) (c.2013delC), and an isogenic control into epicardial cells. While Western blot, flow cytometry, qPCR and immunofluorescence imaging indicated comparable epicardial differentiation efficiencies, RNA-sequencing revealed a profound increased expression of fibroblast and lipid markers only in mutant epicardial cells. These data were corroborated by the spontaneous accumulation of lipid droplets and adipogenic markers in the PKP2 mutant epicardial cells. Single cell sequencing analysis revealed a significant induction of Activating Enhancer-Binding Protein 2 (AP2) family of transcription factors in a subset of PKP2 mutant epicardial cells, which are known to play roles in EMT and lipid biogenesis. siRNA-mediated knock down of AP2 members in mutant epicardial cells significantly reduced the expression of fat and fibroblast markers, suggesting an AP2-mediated fibro-fatty signalling in epicardial cells. The PKP2-dependence of these findings was further validated in healthy iPSC-epicardial cells treated with siRNAs targeting PKP2 which recapitulated the observations made in the mutant cells. Using this human in vitro model system, we were able to show the epicardial role during fibro-fatty tissue replacement upon PKP2 suppression. Ongoing experiments, including studies on explanted ACM hearts and a PKP2 c.2013delC knock-in mouse model, aim at further elucidating the molecular mechanisms of ACM pathogenesis.