Neddylation: from regulatory mechanisms to clinical implications in cancer

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• The review highlights neddylation as a crucial post-translational modification, detailing its regulation of protein function and subsequent alterations in cellular activities. • Providing in-depth analysis of cullins family-related substrates and their biological functions. • Contextualizing within cancer hallmarks, the review comprehensively examines neddylation’s impact on malignant tumor behaviors. • Presenting a systematic evaluation of current clinical trials involving NAE inhibitors aiming to provide novel perspectives and theoretical foundations for clinical oncology. Neddylation is a critical post-translational modification that is frequently hyperactivated in various human cancers. By modifying key substrates such as Cullins and non-Cullin proteins, this pathway plas a central role in regulating protein stability, cellular signaling transduction, and core biological processes. Its dysregulation directly drives tumorigenesis and progression, making it a highly promising therapeutic target. This review aims to systematically elucidate: (1) the processes of neddylation and its regulatory mechanisms on cellular and protein functions; (2) how this pathway promotes malignant progression and tumorigenesis by driving multiple cancer hallmarks; and (3) the development of drugs targeting different neddylation components, along with associated clinical trial progress and toxicity challenges, while also discussing its future prospects in precision oncology. This review constructs a multi-dimensional pathogenic network of neddylation at a systematic level, providing a comprehensive elaboration of its molecular basis in governing key cancer characteristics through modulating protein functions and cellular activities. Simultaneously, we focus on targeted therapeutic strategies against this pathway, analyzing the clinical potential and future directions of novel cancer treatment approaches based on preclinical and clinical evidence from inhibitors such as MLN4924 and TAS4464.