ZBTB1 (zinc finger and BTB domain containing 1) functions as a transcriptional repressor with critical roles in lymphoid development, metabolic stress responses, and DNA damage management. As a transcription factor, ZBTB1 represses cAMP-responsive element (CRE)-mediated transcriptional activation 1 and regulates asparagine synthesis by promoting ASNS transcription under nutrient stress 2. ZBTB1 is essential for T cell development, with targeted disruption causing absent T lymphocytes and a severe combined immunodeficiency phenotype, while also affecting B and NK cell differentiation 3. It plays a key lymphoid-specifying role in hematopoietic stem cells, particularly enriched Kit low HSC subsets, where it supports T cell reconstitution after hematopoietic cell transplantation 45. Beyond developmental functions, ZBTB1 promotes translesion DNA synthesis by facilitating RAD18 loading, PCNA monoubiquitination, and POLH recruitment through chr14 remodeling via KAP-1 phosphorylation 6. Clinically, ZBTB1 acts as a tumor suppressor in breast cancer—its downregulation associates with poor prognosis and tamoxifen resistance, which can be reversed through miR-23b-3p targeting 7. Additionally, ZBTB1 sensitizes leukemia cells to L-asparaginase therapy 2, suggesting therapeutic potential in hematologic malignancies.