UBR3 is an E3 ubiquitin-protein ligase that regulates protein degradation through the ubiquitin-proteasome system across multiple biological processes. As a component of the N-end rule pathway, UBR3 mediates protein ubiquitination and subsequent degradation 1. The protein plays crucial roles in developmental processes, particularly in auditory organ development where it regulates the mono-ubiquitination of non-muscle Myosin II, promoting its interaction with Myosin VIIa, a protein associated with Usher syndrome 2. UBR3 also modulates Hedgehog signaling by promoting poly-ubiquitination and degradation of Costal-2 and Kif7, enhancing signaling in developing tissues 3. In cardiac physiology, UBR3 regulates Nav1.5 sodium channel protein levels through ubiquitin-mediated degradation, affecting cardiac action potential formation 4. Recent large-scale genomic studies have identified UBR3 variants associated with cardiometabolic diseases, neurodevelopmental disorders, and metabolic health, with protein-truncating variants independently increasing body mass index and type 2 diabetes risk 567. Additionally, UBR3 promotes inflammation and apoptosis in intervertebral disc degeneration through the DUSP1/p38 pathway 8, highlighting its broad pathological relevance beyond developmental functions.