Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited heart disease caused primarily by mutations in PKP2, encoding plakophilin-2. No approved therapies target its genetic etiology. This study aimed to develop a human three-dimensional (3D) cardiac organoid model of PKP2-associated ARVC and identify novel therapeutic targets. Methods: Patient-derived peripheral blood mononuclear cells (PBMCs) harboring a heterozygous PKP2 truncating mutation (c.983dupG) were reprogrammed into human induced pluripotent stem cells (hiPSCs) and differentiated into 3D cardiac organoids. Isogenic CRISPR-corrected controls were generated. Phenotypic characterization included immunofluorescence, multi-electrode array (MEA) electrophysiology, and integrated multi-omics (transcriptomics + proteomics). CD44 was identified as a hub gene via protein-protein interaction network analysis and validated through pharmacological inhibition and AAV-mediated PKP2 gene therapy. Results: PKP2-mutant organoids exhibited progressive structural abnormalities from Day 5, including irregular morphology and intercellular disintegration. Immunofluorescence revealed significantly reduced expression of desmosomal proteins (PKP2, DSG2, DSC2, JUP) and elevated α-SMA (fibrosis biomarker). MEA electrophysiology demonstrated wider QRS complexes (28.6 ± 3.4 ms vs. 12.3 ± 1.8 ms, p<0.001) and lower beat rate (42.3 ± 6.1 bpm vs. 78.4 ± 8.2 bpm, p<0.001). Multi-omics analysis identified alterations in MAPK, PI3K/AKT, and PPARγ pathways. Protein-protein interaction network analysis revealed CD44 as the central hub gene (betweenness centrality = 0.342). Pharmacological CD44 inhibition with compound 6 restored electrophysiological function and attenuated fibrosis. AAV-DJ-mediated PKP2 restoration rescued PKP2 expression and normalized CD44 overexpression. Conclusion: This patient-derived 3D cardiac organoid model recapitulates ARVC pathology and identifies CD44 as a previously unreported pathogenic mediator and therapeutic target in PKP2-associated ARVC. These findings support CD44-targeted therapy and PKP2 gene correction as precision treatment strategies