WWP2 is a HECT-type E3 ubiquitin ligase that ubiquitinates diverse substrates and regulates critical cellular processes 1. As an E3 ubiquitin ligase, WWP2 accepts ubiquitin from E2 enzymes and catalyzes K63-linked polyubiquitination of target proteins for proteasomal degradation 2. WWP2 has substrate specificity for multiple proteins including TFEB, PARP1, DDX3X, and CDC20, with functional consequences varying by context 3425. In cancer immunology, WWP2 functions as a negative regulator of MHC-I antigen presentation through a membrane-associated complex with SUSD6 and TMEM127, promoting MHC-I ubiquitination and lysosomal degradation 6. WWP2 has emerged as pathologically important in multiple diseases: in acute kidney injury, WWP2 protects tubular epithelial cells by ubiquitinating CDC20 to promote autophagy 5; in renal fibrosis, WWP2 suppresses myofibroblast profibrotic activation through PGC-1α regulation 7; and in type 2 diabetes, WWP2 protects vascular endothelium by degrading DDX3X 2. In cardiac remodeling, WWP2-mediated PARP1 degradation prevents excessive poly(ADP-ribosyl)ation and myocardial damage 4. These diverse substrate-specific functions establish WWP2 as a multifunctional E3 ligase with significant therapeutic potential 1.