NDFIP1 is an adaptor protein that activates HECT domain-containing E3 ubiquitin ligases (NEDD4, ITCH, NEDD4L) to regulate protein stability and cellular processes 1. Primary functions include immune regulation, neuroprotection, and ion channel modulation. Mechanistically, NDFIP1 recruits E3 ligases to substrates for ubiquitin-dependent degradation. It restricts pro-inflammatory responses by promoting RORC and MAP3K7 degradation in Th17 and effector T cells 1. NDFIP1 negatively regulates antiviral responses via MAVS degradation 2 and controls potassium channel activity (KCNH2, TRESK) through NEDD4L-mediated ubiquitination 34. It regulates iron homeostasis by facilitating ferroportin degradation 5 and protects dopaminergic neurons by regulating VDAC and preventing ferroptosis 6. Disease relevance spans multiple pathologies: NDFIP1 acts as a tumor suppressor in non-small cell lung cancer by promoting TAZ exosomal sorting 7 and reduced NDFIP1 associates with Parkinson's disease pathology 6. Conversely, NDFIP1 upregulation contributes to dopamine agonist resistance in pituitary tumors 8. Genetic variation in NDFIP1 modifies immune cell metabolism in multiple sclerosis 9, highlighting clinical significance for autoimmune disease susceptibility and immunotherapy efficacy in cancer.