UPK3B (uroplakin 3B) is a structural protein primarily functioning as a component of the asymmetric unit membrane (AUM) in terminally differentiated urothelial cells 1. It plays critical roles in AUM-cytoskeleton interactions and contributes to urothelial glycocalyx formation, which prevents bacterial adherence to the bladder epithelium 2. Beyond its canonical urological role, UPK3B serves as a selective marker for mesothelial cells and is expressed in retinal pigment epithelial (RPE) cells during development 34. In RPE differentiation, UPK3B expression is regulated downstream of MYRF transcription factor and is essential for maintaining cell structure and survival during retinal development 5. Clinically, UPK3B immunohistochemistry is diagnostically valuable, showing strong positivity in mesotheliomas (82.1% of epithelioid cases) while being largely absent in other malignancies, making it useful for distinguishing mesotheliomas from other thoracic tumors 1. Emerging evidence suggests UPK3B may function as an immunological biomarker; high expression in pancreatic adenocarcinoma correlates with reduced MHC expression, low immunogenicity, and poor response to immune checkpoint inhibitor therapy 6. Additionally, UPK3B is downregulated during gonadal development as coelomic epithelial cells differentiate into supporting gonadal cells 7, indicating tissue-specific developmental regulation.