PERP (p53 apoptosis effector related to PMP22) is a tetraspan plasma membrane protein with dual roles in apoptosis and epithelial barrier function. As a p53/p63 transcriptional target, PERP mediates apoptosis through caspase-dependent signaling and interaction with SERCA2b at the plasma membrane-endoplasmic reticulum interface to facilitate Ca2+ signaling 1. PERP functions as a component of intercellular desmosome junctions, promoting stratified epithelial cell-cell adhesion and barrier integrity against infection. It is required for tooth enamel development by facilitating ameloblast adhesion during amelogenesis and may regulate downstream amelogenic genes 2. PERP also promotes neutrophil transepithelial migration in response to chemoattractants and bacterial infection [UniProt summary from literature]. Mechanistically, PERP suppresses tumor progression by restricting glucose flux into glycolysis and the TCA cycle, while PERP deficiency enhances anti-tumor immunotherapy efficacy 3. Clinically, biallelic PERP mutations cause erythrokeratodermia variabilis et progressiva and Olmsted syndrome, characterized by keratoderma and increased susceptibility to cutaneous fungal infections due to compromised epidermal barrier function 4. PERP exhibits tumor suppressor properties, with reduced expression in multiple cancers; restoring PERP expression through gene therapy induces apoptosis and suppresses angiogenesis in lung cancer models 5. Low PERP expression correlates with improved immunotherapy response in head and neck squamous cell carcinoma 3.