HECTD3 (HECT domain E3 ubiquitin protein ligase 3) is an E3 ubiquitin ligase that catalyzes ubiquitin transfer to substrate proteins, mediating their proteasomal degradation 1. The enzyme contains functional DOC and HECT domains that enable substrate recognition and ubiquitination 2. HECTD3 regulates diverse cellular processes through substrate-specific modifications: it mediates K27- and K63-linked polyubiquitination of IKKα to promote NF-κB signaling and endothelial inflammation 3, catalyzes K63-linked ubiquitination of PARP1 to stabilize its expression in glioblastoma 4, and performs K33-linked polyubiquitination of PKR to inhibit antiviral responses 5. Notably, HECTD3 also functions independently of its E3 activity by blocking NLRP3-NEK7 interaction through its DOC domain to suppress inflammasome activation 6. In disease contexts, HECTD3 promotes tumor metastasis through endothelial IKKα stabilization, facilitates glioma radioresistance by preventing PRDX1 degradation, and enhances hepatocellular carcinoma lenvatinib resistance via MBNL1 ubiquitination 7. Clinically, HECTD3 emerges as a biomarker elevated in non-small cell lung cancer extracellular vesicles and represents a potential therapeutic target for inflammation-related and malignant diseases 8.