Abstract Body: Introduction: Recent efforts have unveiled the potential for gene therapy to circumvent the progressive and deleterious consequences of arrhythmogenic cardiomyopathy (ACM), a fatal genetic cardiac disease, predominantly impacting genes associated with the desmosomal cell-cell junction. While the desmosomal gene, plakophilin-2 (PKP2), has emerged as a therapeutic target for PKP2 ACM populations, this raises the question as to whether there may be common molecular pathways across different desmosomal mutation backgrounds that could be broadly targeted for therapeutic intervention. Reduction of the ventricular gap junction protein connexin-43 is a common molecular alteration that underlies desmosomal deficits in ACM; however, its specific contribution to driving end-stage structural alterations such as myocardial failure and premature death remains poorly understood. Hypothesis: We hypothesized that connexin-43 restoration could mitigate myocardial end-stage alterations as a mutation-agnostic intervention for ACM. Methods: We generated and exploited human and mouse ACM models with different mutational backgrounds, in combination with viral-based gene therapy to restore connexin-43, aiming to investigate whether connexin-43 gene therapy could circumvent ACM deficits at the molecular, cellular and physiological level. Results: We show that neonatal or adult adeno-associated-viral-mediated connexin-43 gene therapy administration could alleviate the severe bi-ventricular dilatation, dysfunction, arrhythmias as well as prolong lifespan in a severe desmoplakin ACM mouse model. We further found that viral-mediated restoration of full-length connexin-43 could alleviate the baseline and catecholamine induced physiological deficits in ACM human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes harboring PKP2 and desmoglein-2 mutations. At the molecular level, we revealed that connexin-43 restoration in ACM hiPSC-cardiomyocytes and mouse hearts could trigger the upregulation of desmosomal gene expression, proteins and their re-localization to the cardiac cell-cell junction, to support their mechanical coupling. Conclusion: These data suggest non-canonical functions of connexin-43 in mechanical modulation and highlight a therapeutic target to reassemble the desmosome and treat diverse ACM populations.