Multidimensional roles of NEDD9 in cancer progression: From molecular regulation to clinical translation

NEDD9 (Neural precursor cell expressed developmentally downregulated 9) is a scaffolding protein that plays a central role in coordinating multiple oncogenic signaling pathways involved in tumor progression. It regulates diverse cellular processes, including cell migration, epithelial-mesenchymal transition, stemness, and therapeutic resistance, primarily through its function as a signaling integrator. Despite increasing evidence supporting the importance of NEDD9 in cancer, several key challenges remain, including a lack of systems-level understanding of its regulatory networks, incomplete characterization of its role in tumor immune microenvironment modulation, and difficulties in developing effective therapeutic strategies targeting this scaffold protein. In this review, we provide a comprehensive and integrative analysis of NEDD9 by systematically linking its structural features, multilayered regulatory mechanisms, diverse biological functions, and clinical relevance within a unified conceptual framework. We further emphasize its role as a dynamic signaling hub in cancer progression. Finally, we highlight key research priorities, including the need for multi-omics integration, improved understanding of context-dependent functions, and the development of innovative strategies targeting NEDD9-associated signaling and interaction networks, which may facilitate its translation into clinical applications.