GJB4 encodes gap junction protein beta 4 (connexin 30.3), a structural component of gap junctions that form dodecameric channels connecting adjacent cell cytoplasm 1. These channels permit diffusion of small molecules and ions between cells through intercellular communication 1. GJB4 variants cause erythrokeratodermia variabilis et progressiva (EKVP), a rare hereditary skin disorder characterized by hyperkeratotic plaques and erythematous patches 2. GJB4 mutations elicit multiple molecular defects including impaired gap junction formation, dysregulated hemichannel function, and altered channel kinetics 2. Specific mutations in transmembrane domains (T85P, F137L) affect voltage gating and channel closure kinetics, while amino-terminal mutations may interfere with connexin selectivity 3. Beyond dermatology, GJB4 shows unexpected roles in malignancy. Upregulated GJB4 expression in pancreatic cancer correlates with poor prognosis and promotes tumor growth through MET-AKT pathway activation, with GJB4 knockdown inducing ferroptosis and suppressing metastasis 45. Similarly, in lung cancer, elevated GJB4 promotes metastasis and chemoresistance via Src activation and serves as a prognostic biomarker 6. Conversely, GJB4 overexpression in pancreatic islet cells impairs insulin secretion and cell proliferation, suggesting involvement in type 2 diabetes pathogenesis 7.