RWDD3 (RWD domain-containing 3), also termed RSUME, is a SUMO conjugation enhancer that promotes protein sumoylation through direct interaction with the E2-SUMO conjugase UBC9 1. The protein increases SUMO transfer to specific targets including HIF1A, NFKBIA, NR3C1, and TOP1 by stabilizing the E1-E2 enzyme complex and facilitating thioester bond formation 2. RWDD3 expression is induced by cellular stress including hypoxia and heat shock, with upregulation observed in multiple tissues including pituitary, kidney, heart, and pancreas 23. RWDD3 plays critical roles in cellular signaling by enhancing sumoylation of key regulatory proteins. It stabilizes the NF-κB inhibitor NFKBIA, suppressing NF-κB transcriptional activity, and promotes HIF1A sumoylation during hypoxia, enhancing its transcriptional activity and VEGFA expression 2. Additionally, RWDD3 suppresses VHL-mediated ubiquitination of HIF proteins, preventing their degradation 3. Clinically, RWDD3 dysregulation is implicated in multiple malignancies. High RWDD3 expression correlates with poor prognosis in glioblastoma, pituitary tumors, and non-small cell lung cancer 45. In glioblastoma, RWDD3 knockdown inhibits proliferation and invasion via PI3K/AKT pathway suppression 5. RWDD3-enriched extracellular vesicles promote lymph node metastasis in NSCLC through circular RNA transport mechanisms 6. RWDD3 also shows potential involvement in myocardial ischemia response 7, suggesting broader pathophysiological relevance beyond cancer.