HECW1 (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1) is a NEDD4 family E3 ubiquitin ligase that mediates ubiquitination and degradation of multiple substrates. Primary substrates include DVL1, which functions as a Wnt/β-catenin pathway activator 1, and ZNF350, a transcriptional regulator 2. HECW1 also targets mutant SOD1 in familial ALS contexts and interacts with HIPK2 to regulate AKT signaling 3. Mechanistically, HECW1 negatively regulates Wnt/β-catenin signaling through DVL1 ubiquitination 1 and promotes ferroptosis in gliomas via the ZNF350/NCOA4 axis 2. In gastric cancer, HECW1-mediated HIPK2 degradation activates AKT signaling and epithelial-mesenchymal transition 3. Clinically, HECW1 shows context-dependent roles. In gastric and bladder cancers, elevated HECW1 expression correlates with poor prognosis and promotes tumorigenesis 456. Conversely, in cervical cancer, HECW1 suppresses cell growth 1. HECW1 variants associate with IgA nephropathy through IgA1 glycosylation regulation 7. In ALS, HECW1 variants and overexpression contribute to neuronal death and TDP-43 mislocalization 8, suggesting roles in neurodegenerative disease pathophysiology.