NEDD4L is an E3 ubiquitin ligase that regulates diverse cellular processes through polyubiquitination-mediated protein degradation. As a HECT family ubiquitin ligase, NEDD4L catalyzes lysine and cysteine ubiquitination of multiple targets, mediating their proteasomal degradation 1. A primary function involves negative regulation of ion channels and transporters; NEDD4L ubiquitinates and promotes internalization of sodium channels (SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8), potassium channels (KCNA3/Kv1.3, KCNH2, KCNQ2/Kv7.2, KCNQ3/Kv7.3), and other transporters including ENaC and EAAT1. In diabetic nephropathy, NEDD4L expression increases in renal tubular cells, correlating with enhanced potassium secretion 2. In intestinal homeostasis, NEDD4L maintains epithelial cell integrity by regulating SLC3A2-dependent ferroptosis; NEDD4L deficiency exacerbates colitis and colorectal tumorigenesis through ferroptosis dysregulation 3. NEDD4L exhibits context-dependent tumor effects: it suppresses breast cancer progression by ubiquitinating YAP1 and CTR1, blocking pro-tumorigenic signaling 45, yet paradoxically promotes endothelial cell angiogenesis via Akt/Erk/eNOS pathways 6. Additionally, NEDD4L regulates ferroptosis in lung cancer through SLC7A11 degradation 7. These multifaceted functions position NEDD4L as a critical regulator of cellular homeostasis with therapeutic relevance across metabolic, inflammatory, and malignant diseases 8.