PKP1 is a desmosomal plaque protein essential for cell-cell adhesion and epidermal barrier function. It localizes at the cell membrane, cytoplasm, and nucleus, where it regulates desmosome assembly and stability by controlling the expression, localization, and clustering of desmogleins and other junction proteins 1. PKP1 also functions in translation by recruiting the initiation factor EIF4A1 to promote cap-dependent translation and cell proliferation. At the population level, PKP1 exhibits clinical pathogenicity distinct from population-level constraint: homozygous loss-of-function mutations cause ectodermal dysplasia–skin fragility syndrome, characterized by skin erosions, perioral fissuring, palmoplantar hyperkeratosis, and variable ectodermal abnormalities including hypotrichosis, hypohidrosis, and nail dystrophy 2. Notably, PKP1 mutations do not result in cardiac pathology because the gene is not expressed in the heart. In cancer, PKP1 exhibits context-dependent roles. In squamous cell lung cancer, PKP1 is overexpressed and creates a feedforward loop with MYC, enhancing MYC translation while MYC promotes PKP1 transcription 3. In esophageal squamous cell carcinoma, the CCND1-PKP1-JUP-ANKRD12 prognostic signature predicts patient survival and drug sensitivity, with PKP1 expression correlating with EGFR expression across multiple cancers 4. Conversely, PKP1 downregulation in prostate cancer may permit tumor progression through upregulation of SPOCK1, suggesting a tumor-suppressive function in this context 5. These contrasting roles in different malignancies indicate PKP1 warrants investigation as a context-specific therapeutic target.