CASP8AP2 (caspase 8 associated protein 2) is a multifunctional protein with critical roles in apoptosis, transcriptional regulation, and cell cycle control. Mechanistically, CASP8AP2 participates in TNF-induced blockade of glucocorticoid receptor transactivation 1 and acts as a downstream mediator for caspase 8-induced NF-κB activation 2. It is required for caspase 8 activation in FAS-mediated apoptosis 2 and plays essential roles in histone gene transcription by facilitating 3' end processing of histone pre-mRNAs 3. CASP8AP2 interacts with E2F3a to collaboratively regulate replication-dependent histone expression and S phase progression 4, and forms complexes with CtBP2 and ZEB2 to suppress stemness-related gene expression in leukemia 5. Clinically, CASP8AP2 is a significant prognostic biomarker in hematologic malignancies. Low CASP8AP2 expression correlates with poor outcomes and increased relapse risk in acute lymphoblastic leukemia 67, and gene deletion predicts poor prognosis in T-ALL 8. Genomic deletion at 6q15 involving CASP8AP2 occurs in approximately 11% of T-ALL cases 9. Beyond leukemia, CASP8AP2 was identified as essential for lung adenocarcinoma viability through the AP-1 pathway 10, and promoter methylation contributes to drug resistance in cancer cells 11.