AI-Driven Validation of PKP3 as a Multifaceted Oncogenic Hub

Abstract

Artificial intelligence–assisted prompting offers a transformative strategy for rapidly identifying and contextualizing biological targets. Using Swalife PromptStudio, we present a case study of Plakophilin 3 (PKP3)which is a desmosomal protein that functions as both a structural anchor and a signaling regulator, with emerging significance in human disease. Genetic evidence reveals a dual role: rare homozygous loss-of-function variants cause ectodermal dysplasia/skin fragility syndrome, confirming its essential role in epithelial integrity, while common regulatory variants identified by genome-wide association studies link PKP3 overexpression to psoriasis risk. Additionally, somatic copy-number amplifications in carcinomas drive PKP3 upregulation, correlating with tumor progression and poor prognosis. Despite modest effect sizes for common variants, the combination of replicated GWAS signals, pathogenic rare mutations, and cancer amplifications provides strong validation. These findings establish PKP3 as a genetically anchored, translationally relevant therapeutic target in inflammatory and oncologic indications.