HECTD1 is an E3 ubiquitin-protein ligase that plays crucial roles in development, cellular homeostasis, and disease pathogenesis. The protein accepts ubiquitin from E2 enzymes and directly transfers it to target substrates, catalyzing both protein degradation and regulatory modifications 1. HECTD1 mediates Lys-63-linked polyubiquitination of HSP90AA1, reducing its secretion and regulating cranial mesenchyme cell migration essential for neural tube closure 2. The enzyme also ubiquitinates and degrades ZNF622 in hematopoietic cells, promoting stem cell renewal 1. HECTD1 is critical for neurodevelopment, with conditional knockout in mice causing microcephaly, hippocampal malformations, and corpus callosum agenesis 3. The protein regulates autophagy by ubiquitinating Rubicon for proteasomal degradation, which is important in osteoarthritis pathogenesis 4. Disease relevance includes neural tube defects, with rare missense variants identified in human cases showing reduced ability to suppress eHSP90 secretion 2, and neurodevelopmental disorders, with 14 individuals carrying pathogenic variants displaying autism, ADHD, and epilepsy 3. HECTD1 also functions in cancer, diabetes complications, and depression through various substrate interactions.