ZBED2 is a zinc finger transcriptional repressor that functions as a master regulator of cell identity across multiple tissues. The protein operates as a sequence-specific DNA-binding transcription factor that antagonizes interferon regulatory factor 1 (IRF1) at shared promoter elements containing the consensus sequence 5'-[CA]GAA[AC]C[CT]-3', thereby suppressing interferon-stimulated gene expression 1. In keratinocytes, ZBED2 promotes the basal undifferentiated state; experimental depletion of ZBED2 induces keratinocyte differentiation, indicating its role in maintaining stemness through repression of differentiation programs 2. ZBED2 is aberrantly expressed in pancreatic ductal adenocarcinoma (PDA), where elevated expression is associated with poor survival outcomes and the aggressive squamous molecular subtype 1. In this context, ZBED2 suppresses interferon responses and promotes lineage plasticity, enhancing cell motility and invasion 1. Beyond PDA, ZBED2 is also dysregulated in bladder cancer, where it functions as a master transcription factor for basal identity and cooperates with FOXA1 to inhibit inflammatory responses via STAT2 suppression 3. Additionally, ZBED2 expression is associated with poor prognosis in lung squamous cell carcinoma and is differentially methylated in HPV-induced warts, suggesting broader roles in epithelial malignancies 4. These findings establish ZBED2 as a critical regulator of lineage identity with significant implications for cancer progression and therapy.