DSG3 (desmoglein 3) is a transmembrane adhesion molecule that functions as a core component of desmosomes, mediating cell-cell adhesion in epithelial tissues. It is required for desmosome assembly and maintenance of epithelial barrier integrity, particularly in the basal and suprabasal layers of the epidermis and hair follicles. Beyond adhesion, DSG3 participates in mechanotransduction by facilitating YAP1 localization at the plasma membrane in keratinocytes, thereby regulating cell proliferation and contractility through F-actin organization. DSG3 is pathologically relevant in pemphigus vulgaris, a B cell-mediated autoimmune disease in which anti-DSG3 autoantibodies disrupt desmosomal adhesion and trigger keratinocyte acantholysis 1. Multiple antigen-specific immunotherapies targeting DSG3-autoreactive cells are in development: DSG3-chimeric autoantigen receptor T cells (DSG3-CAART) 2, engineered Dsg3-specific induced regulatory T cells (S/F-iTreg) 3, and Dsg3-Fc fusion proteins 4 have demonstrated preclinical efficacy in reducing anti-DSG3 B cell burden and autoantibody production without systemic immunosuppression. Additionally, the phosphodiesterase 4 inhibitor apremilast rescues pemphigus autoantibody-induced loss of keratinocyte adhesion through Epac1-dependent mechanisms 5. Beyond autoimmunity, DSG3 exhibits oncogenic functions in muscle-invasive bladder cancer, where elevated expression activates the AKT/GSK3β/β-catenin pathway to promote epithelial-mesenchymal transition, cancer stemness, and metastasis 6.