MYCBP2 is an atypical E3 ubiquitin ligase with distinctive threonine/serine esterification activity, unlike conventional lysine-targeting E3 ligases 1. It contains two essential catalytic cysteine residues that relay ubiquitin to substrates via thioester intermediates and interacts with E2 enzymes UBE2D1, UBE2D3, UBE2E1, and UBE2L3 1. Functionally, MYCBP2 is critical for neurodevelopment, particularly axon growth and navigation. Loss-of-function MYCBP2 variants cause a neurodevelopmental disorder featuring corpus callosum defects, developmental delay, intellectual disability, epilepsy, and autistic features 2. MYCBP2 mediates Wallerian axon degeneration through NMNAT2 destabilization and regulates EPHB2 receptor signaling, stabilizing this protein for efficient signal transduction 34. Beyond neurodevelopment, MYCBP2 regulates diverse cellular processes including TSC2 degradation, circadian gene expression via NR1D1 ubiquitination, HNF4α-mediated lipid metabolism, and TRPV1 internalization. In hepatocellular carcinoma, MYCBP2 acts as a potential tumor suppressor by promoting HNF4α degradation and reprogramming lipid metabolism 5. These findings identify MYCBP2 as a multifunctional signaling hub with emerging therapeutic potential in neurodevelopmental and metabolic disorders.