HECTD4 (HECT domain E3 ubiquitin protein ligase 4) is a conserved E3 ubiquitin ligase that functions as a tumor suppressor and regulator of metabolic and developmental processes. As an E3 ubiquitin ligase, HECTD4 mediates ubiquitin conjugation to target proteins for proteasomal degradation 1. Its primary substrates include cyclooxygenase-2 (COX-2) and the MKK7 kinase, with HECTD4 suppressing COX-2-dependent anchorage-independent proliferation and metastasis in breast cancer 1. Additionally, HECTD4 stabilizes and prevents ubiquitination of IGF2BP3, an oncogenic protein, suggesting context-dependent substrate specificity in tumor progression 2. Genetically, HECTD4 variants are associated with caffeine metabolism and intake, with the rs2074356 polymorphism showing ethnicity-specific effects (associated with East Asian populations) 3. This variant also modulates the relationship between coffee consumption and obesity risk in Korean populations, with genotype-dependent effects on obesity susceptibility 4. Biallelic pathogenic variants in HECTD4 cause neurodevelopmental disorders with seizures and movement abnormalities, overlapping with Angelman syndrome phenotypes 5. HECTD4 was identified as a high-confidence neurodevelopmental disorder candidate gene through integrated analysis of de novo variants 6. Nonsynonymous variants are more frequently observed in oral cancer patients who are elderly nonsmokers 7. These findings establish HECTD4 as a pleiotropic gene regulating cancer progression, neurodevelopment, and metabolic traits through ubiquitin-mediated protein degradation.