HERC1 is a large HECT-family E3 ubiquitin ligase (>520 kDa) constitutively expressed in the brain that functions as a guanine nucleotide exchange factor (GEF) for Arf and Rab proteins, regulating membrane trafficking through interactions with clathrin and phosphatidylinositol 4,5-bisphosphate 1. As an E3 ligase, HERC1 ubiquitinates diverse substrates including C-RAF, MKK3, NCOA4, and deoxycytidine kinase, targeting them for proteasomal degradation 234. Neurologically, HERC1 mutations cause cerebellar ataxia, motor coordination loss, and intellectual disability through dysregulated autophagy and Purkinje cell death 15. In cancer contexts, HERC1 functions protectively: it suppresses non-small cell lung cancer proliferation and promotes ferroptosis via C-RAF degradation 4, while in acute myeloid leukemia, HERC1 overexpression confers resistance to nucleoside analogs, and HERC1 loss enhances drug sensitivity 3. Conversely, a circular RNA derived from HERC1 promotes lung cancer progression by sequestering FOXO1 in the cytoplasm 6. HERC1 also regulates cell migration through RAF-dependent MKK3/p38 signaling modulation 2, and variants associate with schizophrenia risk 7.