DSG3 (desmoglein 3) is a transmembrane glycoprotein and critical component of desmosomal cell-cell junctions essential for epithelial integrity 1. It functions as a calcium-dependent adhesion molecule required for desmosome assembly and maintenance of the epithelial barrier, particularly in basal and suprabasal layers of the epidermis 1. DSG3 regulates keratinocyte adhesion through multiple mechanisms: it organizes cortical F-actin bundles via RAC1 interaction, promotes YAP1 membrane localization in response to mechanical strain, and modulates desmoplakin-associated plaque protein stability 2. Additionally, DSG3 suppresses keratinocyte migration by inhibiting p38MAPK signaling, thereby moderating wound healing responses 3. DSG3 is pathologically relevant in pemphigus vulgaris, an autoimmune blistering disorder where circulating autoantibodies target DSG3 and DSG1, disrupting desmosomal adhesion and causing acantholysis 145. Loss of DSG3-mediated adhesion can be rescued through Epac1-dependent cAMP signaling or antigen-specific B cell depletion strategies 647. Emerging evidence demonstrates unexpected roles for DSG3 in bladder cancer progression through AKT/GSK3β/β-catenin pathway activation, promoting epithelial-mesenchymal transition, cancer stemness, and metastatic potential 8. These findings reveal DSG3 functions beyond adhesion in cell signaling and cancer biology, with potential implications for both autoimmune and malignant disease treatment.