UBE4B (ubiquitination factor E4B) is a dual-function E3/E4 ubiquitin ligase that catalyzes polyubiquitin chain assembly on protein substrates 1. As an E4 ligase, UBE4B elongates ubiquitin chains initiated by other E3 ligases, directing substrates for proteasomal degradation 2. Mechanistically, UBE4B interacts with E3 ligases and substrates to mediate their ubiquitination; for example, it cooperates with MDM2 to polyubiquitinate p53, enabling its proteasomal degradation and suppressing p53-dependent apoptosis 1. UBE4B also targets mitofusins for degradation during mitochondrial stress responses 2 and regulates FAT4 ubiquitination in gastric cancer 3. Disease relevance is substantial. UBE4B haploinsufficiency contributes to 1p36 deletion syndrome, characterized by developmental delay, intellectual disability, seizures, and cardiac defects 4. In cancer, UBE4B is overexpressed in gastric cancer and hepatocellular carcinoma, where it promotes proliferation and metastasis through substrate degradation 35. UBE4B also participates in neurodegenerative disease pathways, including tau seed amplification in tauopathies and Charcot-Marie-Tooth disease-associated mitofusin dysfunction 26. Clinically, UBE4B represents a promising therapeutic target: inhibiting UBE4B-MDM2 interactions could restore p53 function for cancer treatment 1, while targeting UBE4B-dependent pathways may address cancer metastasis and neurodegeneration 35.