ZFP64 is a C2H2-type zinc finger transcription factor that functions as a coactivator in Notch signaling and regulates mesenchymal cell differentiation 1. As a transcriptional regulator, ZFP64 binds directly to promoters of target genes including NOTCH1 targets (Hes1, Hey1), immune checkpoint molecules (PD-1, CTLA-4), and metabolic enzymes (HK2, ENO2, ALDOC), thereby controlling their expression 123. In cancer contexts, ZFP64 drives tumorigenesis through multiple mechanisms. In hepatocellular carcinoma, PKCα-mediated phosphorylation of ZFP64 at S226 promotes its nuclear translocation and CSF1 transcriptional activation, shifting macrophage polarization toward an M2 immunosuppressive phenotype and conferring anti-PD1 resistance 4. In breast cancer, ZFP64 promotes stem cell-like properties and glycolysis-dependent tumorigenesis via transcriptional activation of glycolytic genes 3. In triple-negative breast cancer, histone lactylation enhances ZFP64 expression, which then activates ferroptosis-suppressing genes (GCH1, FTH1) to promote doxorubicin resistance 5. ZFP64::NCOA2/3 gene fusions define an aggressive spindle cell rhabdomyosarcoma subtype 67. Clinically, ZFP64 overexpression correlates with poor prognosis in breast cancer and esophageal cancer 32. Conversely, ZFP64 depletion increases fetal hemoglobin expression, suggesting therapeutic potential for hemoglobinopathies 8.