EVPL (envoplakin) is a membrane-associated protein that functions as a structural component of the cornified envelope in keratinocytes, linking desmosomes and keratin intermediate filaments to the cornified envelope 1. The protein is homologous to desmoplakin and bullous pemphigoid antigen 1, positioning it as a critical architectural element in epidermal organization 1. At the molecular level, EVPL contains N-terminal and linker subdomains that serve as epitopes for autoantibodies, with major antigenic regions localized to the N-terminus (aa1-141) and linker region (aa1684-1784) 2. The protein's expression in epidermal and oesophageal keratinocytes suggests roles in barrier function across multiple tissues 1. Clinically, EVPL is genetically linked to focal nonepidermolytic palmoplantar keratoderma (tylosis) on chromosome 17, a condition associated with increased oesophageal cancer risk, implicating loss of envoplakin function in disease pathogenesis 1. Additionally, EVPL has emerged as a core comorbidity gene in type 2 diabetes mellitus and colorectal cancer, with upregulation associated with altered immune responses 3. Recent evidence suggests pollution-related DNA methylation changes affecting EVPL expression may increase gastrointestinal disease risk, including gastroesophageal reflux disease and gastric ulcer 4.