CNOT3 is a core subunit of the CCR4-NOT deadenylase complex, a major regulator of mRNA stability and gene expression. As a component of this complex, CNOT3 mediates bulk mRNA degradation, miRNA-mediated repression, and translational control 1. Mechanistically, CNOT3 recognizes stalled ribosomes during translation elongation through interaction with specific arginine tRNAs, which promote its recruitment to translating ribosomes and accelerate mRNA degradation in a codon usage-dependent manner 12. CNOT3 also inserts into the ribosomal E site and locks the L1 stalk to enforce translational stalling 2. Beyond mRNA decay, CNOT3 is essential for maintaining embryonic stem cell identity by repressing trophectoderm differentiation factors 3. Clinically, CNOT3 dysfunction is implicated in two distinct disease contexts. Heterozygous loss-of-function mutations in CNOT3 cause intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF), affecting 87% of patients with mild-to-moderate intellectual disability and behavioral issues 45. Additionally, elevated CNOT3 expression correlates with unfavorable outcomes in acute myeloid leukemia patients; CNOT3 promotes leukemogenesis by enhancing translation efficiency of c-MYC and other oncogenic targets through selective codon usage-dependent mechanisms 6. These findings establish CNOT3 as a critical regulator of post-transcriptional gene expression with significant roles in neural development and cancer pathogenesis.