ZNF281 is a zinc finger transcription factor that plays critical roles in stem cell differentiation, embryonic development, and cancer progression. In embryonic stem cells, ZNF281 functions as a transcriptional repressor that regulates differentiation by mediating autorepression of NANOG through binding to its promoter and recruiting the NuRD deacetylase complex 1. The protein also regulates multipotent stem cell fate, where ZNF281 knockdown promotes spontaneous osteochondrogenic differentiation while maintaining stem cell characteristics through transcriptional regulation of β-CATENIN 2. ZNF281 acts as an epithelial-mesenchymal transition (EMT)-inducing transcription factor, with expression controlled by SNAIL and inhibited by tumor suppressive miR-34a in a p53-dependent manner 1. In cancer contexts, ZNF281 promotes tumor progression through multiple mechanisms: it enhances proliferation and invasion in pancreatic cancer by directly binding β-catenin and activating Wnt/β-catenin signaling 3, inhibits neuronal differentiation in neuroblastoma while serving as a poor prognostic marker 4, and contributes to chemotherapy resistance in gastric cancer 5. ZNF281 also facilitates cancer-associated fibroblast-mediated premetastatic niche formation in breast cancer through regulation of CCL2/CCL5 expression 6. These findings establish ZNF281 as a key regulator linking stem cell biology, differentiation control, and oncogenesis.