CPSF3 is a multifunctional endonuclease and core component of the cleavage and polyadenylation specificity factor (CPSF) complex that regulates 3'-end processing of pre-mRNAs and histone transcripts 1. As an mRNA 3'-end-processing endonuclease, CPSF3 recognizes polyadenylation signals and catalyzes cleavage, enabling poly(A) addition and transcriptional termination 2. It also possesses 5' to 3' exonuclease activity for degrading downstream cleavage products in histone pre-mRNA processing 3. CPSF3 regulates alternative polyadenylation (APA), controlling 3'UTR length and miRNA accessibility to modulate gene expression 45. Additionally, CPSF3 is required for S-phase cell cycle progression 1. Clinically, CPSF3 is significantly overexpressed across multiple cancers including acute myeloid leukemia, Ewing's sarcoma, ovarian cancer, esophageal squamous cell carcinoma, glioblastoma, pancreatic cancer, and bladder cancer, correlating with poor patient prognosis 62437. CPSF3 inhibition via small-molecule inhibitors (JTE-607, benzoxaboroles) induces transcriptional readthrough, reduces histone expression, triggers apoptosis, and suppresses tumor growth in multiple cancer models 68. A homozygous pathogenic variant in CPSF3 causes neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, underscoring its essential role in normal development.