Dsg3, also known as DG3, is a transmembrane glycoprotein primarily found in desmosomes of keratinocytes in squamous epithelium. It mediates cell adhesion within desmosomes, playing a crucial role in maintaining the integrity of the skin and mucosa [2,3]. Dysregulation of Dsg3-related processes can lead to various diseases, highlighting its biological importance.

In pemphigus vulgaris, an autoimmune blistering disease, autoantibodies against Dsg3 disrupt desmosomes and cellular cohesion. Different epitope-specific autoantibodies have varying pathogenic effects. For example, the murine IgG AK23, directed against the EC1 domain of Dsg3, is more effective in causing loss of cell adhesion and induces Dsg3 depletion, phosphorylation of Src, p38MAPK, and Akt, while 2G4 (against EC5 domain) has milder effects [1]. The diversity of serum anti-DSG3 IgG subclasses impacts pemphigus activity and can predict relapses after treatment with rituximab [4]. In cancer, Dsg3 shows differential expression. It is overexpressed in head and neck cancer, and its inhibition reduces cell growth, colony formation, migration, and invasion in vitro and tumor growth in vivo, suggesting it as a potential therapeutic target [5]. In rectal adenocarcinoma, DSG3 expression negatively correlates with tumor regression and has an independent negative impact on survival, serving as a prognostic factor and predictor for neoadjuvant concurrent chemoradiotherapy response [6].

In conclusion, Dsg3 is essential for maintaining the integrity of the skin and mucosa through its role in cell adhesion. Studies on Dsg3 in disease models, especially in pemphigus and cancer, have provided insights into its functions and potential as a therapeutic target. Understanding Dsg3-related mechanisms in these diseases may offer new strategies for treatment.