NEDD4-1: from molecular mechanisms to clinical translation in human diseases

Neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1), the founding member of the HECT family of E3 ubiquitin ligases, mediates substrate protein ubiquitination through its C2, WW, and HECT domains. It plays a key role in protein degradation via both the ubiquitin-proteasome system (UPS) and the lysosomal pathway. Recent evidence highlights the complexity of NEDD4-1's functions. This review synthesizes advancements in the regulatory mechanisms of NEDD4-1, emphasizing its critical involvement in cancer initiation and progression. Beyond oncology, it highlights NEDD4-1's vital functions in maintaining nervous system integrity, metabolic balance, cardiovascular health, and immune regulation. By examining the structural features, physiological roles, expression profiles in various diseases, molecular regulatory networks, and potential clinical applications of NEDD4-1, this review provides a comprehensive framework for understanding its biological mechanisms and advancing targeted therapeutic strategies.