CASC3 is a core component of the exon junction complex (EJC) that plays critical roles in post-transcriptional gene regulation. As a spliceosome component, CASC3 is deposited at exon-exon junctions during pre-mRNA splicing 12. However, CASC3 functions distinctly from other EJC core proteins as a peripheral EJC protein 3. The EJC undergoes compositional remodeling during mRNA metabolism, transitioning from RNPS1-containing to CASC3-containing complexes, which alters mRNP structure and specifies distinct phases of EJC-dependent nonsense-mediated mRNA decay (NMD) 4. CASC3 promotes transcriptome-wide activation of NMD by equipping the EJC with persistent ability to communicate with cytoplasmic NMD machinery, stimulating endonucleolytic cleavage at termination codons 3. Beyond splicing, CASC3 influences mRNA export, localization, and translation efficiency. In the central nervous system, EJC components including CASC3 control mitosis and symmetric/asymmetric cell divisions; reduced EJC levels cause microcephaly 5. Dysregulation of CASC3 is implicated in hepatocellular carcinoma, where CASC3 overexpression promotes cell proliferation, migration, invasion, and glycolysis via miR-124-1 and miR-490-5p regulatory axes 67. Additionally, AKT signaling can modulate NMD through CASC3-containing EJCs in contexts like Fragile X syndrome 8.