UBR1 is an E3 ubiquitin ligase that functions as a core component of the N-end rule pathway, recognizing proteins bearing destabilizing N-terminal residues (N-degrons) and targeting them for proteasomal degradation 1. It recognizes both type-1 N-degrons (positively charged amino acids) and type-2 N-degrons (bulky hydrophobic residues), with the requirement that N-termini remain unacetylated for recognition 2. UBR1 also binds branched-chain amino acids like leucine and isoleucine, functioning as a negative regulator of mTOR signaling to control cell growth and energy metabolism 34. Additionally, UBR1 mediates lipid droplet protein degradation and regulates hepatic lipid metabolism in response to dietary amino acids 4. During oxidative stress, UBR1 activity is inhibited through modification by lipid peroxidation products, allowing lipid droplet accumulation for antioxidant protection 5. Loss-of-function UBR1 mutations cause Johanson-Blizzard syndrome, an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, facial anomalies, hearing loss, and developmental impairment 6. Recently, UBR1 was identified as a sex-dependently regulated ACE2 ubiquitin ligase involved in hypertension pathogenesis 7. Emerging therapeutic applications include arginine-based PROTACs utilizing UBR1 for targeted α-synuclein degradation in Parkinson's disease 8.