HERC3 is an E3 ubiquitin ligase that plays diverse regulatory roles in cellular processes through both enzymatic and non-enzymatic mechanisms 1. The protein functions primarily in protein quality control and degradation pathways, including ER-associated degradation (ERAD) where it recognizes exposed membrane-spanning domains of misfolded proteins like CFTR 2. HERC3 mediates ubiquitination and proteasomal degradation of multiple substrates including RPL23A, EIF5A2, SMAD7, and MM1, thereby regulating cell proliferation, epithelial-mesenchymal transition, autophagy, and senescence 3456. Remarkably, HERC3 can also function independently of its ligase activity, as demonstrated in NF-κB regulation where it forms complexes with ubiquilin-1 and the proteasome to facilitate RelA degradation 7. Similarly, HERC3 promotes YAP/TAZ stability by binding β-TrCP and blocking YAP/TAZ ubiquitination without requiring enzymatic activity 8. Clinically, HERC3 shows tumor suppressor activity in colorectal cancer and glioblastoma, with downregulation associated with poor prognosis 35. The protein localizes to cytosol and vesicular structures and is itself regulated by ubiquitination and proteasomal degradation 1.