UBE4A (ubiquitination factor E4A) is a U-box-type E3/E4 ubiquitin ligase that catalyzes Lys-48-linked polyubiquitination of diverse protein substrates 1. As an E4 ligase, UBE4A mediates assembly of polyubiquitin chains on proteins previously ubiquitinated by other E3 ligases, functioning in the endoplasmic reticulum-associated degradation (ERAD) pathway 2. UBE4A is predominantly expressed in skeletal muscle, kidney, and liver, localizing to both nuclear and cytoplasmic compartments 1. Functionally, UBE4A regulates metabolic homeostasis and insulin signaling by catalyzing K63-linked ubiquitination of Akt and its activator APPL1, promoting insulin-induced Akt activation 3. The enzyme also ubiquitinates the transcription factor NRF1, facilitating its ERAD-mediated cleavage and enabling proteasomal gene expression 2. Additionally, UBE4A ubiquitinates PD-L1 for sorting onto tumor-derived extracellular vesicles, contributing to anti-PD-1 therapy resistance 4, and mediates apoA-I degradation in hepatocytes 5. Disease relevance is substantial: UBE4A deletion impairs insulin signaling and exacerbates obesity, hyperinsulinemia, and non-alcoholic fatty liver disease in mice 3. UBE4A is located in neuroblastoma deletion regions with identified mutations in tumor samples 6. In colorectal cancer, PTBP3-mediated stabilization of UBE4A mRNA promotes P53 degradation and cell proliferation 7. Age-dependent upregulation of UBE4A correlates with muscle proteostasis decline during aging 8.