ZNF398 is a transcriptional regulator belonging to the KRAB domain-containing zinc finger protein family, functioning primarily as a transcriptional repressor 1. In human pluripotent stem cells (hPSCs), ZNF398 acts as a transcriptional activator mediating pluripotency and epithelial character downstream of TGF-beta signaling 2. Mechanistically, ZNF398 binds active promoters and enhancers together with SMAD3 and the histone acetyltransferase EP300 to enable TGF-beta target gene transcription 2. During epiblast development, ZNF398 acts downstream of TGFβ1 to activate the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2 3. The p52 isoform of ZNF398 (also called p52-ZER6) is predominantly expressed in brain tissue and suppresses the antioxidant metallothionein-3, thereby increasing reactive oxygen species in neuronal cells 1. Upregulation of p52-ZER6 in Alzheimer's disease models correlates with reduced MT3 levels, suggesting a potential pathological mechanism in neurodegeneration 1. Additionally, p52-ZER6 overexpression enhances MDM2-p53 binding and reduces tumor cell sensitivity to MDM2-p53 inhibitors, identifying it as a potential cancer biomarker 4. ZNF398 has clinical implications for regenerative medicine applications and understanding neurodegenerative disease pathogenesis.