Neddylation: from regulatory mechanisms to clinical implications in cancer

Sep 23, 2026

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Neddylation is a critical post-translational modification frequently hyperactivated across human cancers. By modifying core substrates including Cullins and multiple non-Cullin proteins, the pathway centrally controls protein stability, cellular signaling transduction, and essential biological processes. Dysregulation of neddylation directly drives tumorigenesis and malignant progression, establishing it as a promising therapeutic target.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages26

Reading Time1 h 6 min

AccessFree to download

Introduction

The role of neddylation in post-translational modifications

The processes of neddylation and deneddylation

Neddylation crosstalk with other post-translational modifications

Functional mechanisms of neddylation

Modulation of protein function

Regulation of cullins and non-cullins

Regulation of protein stability

Regulation of protein–protein interactions

Regulation of subcellular localization

Journal of Advanced Research 86 (2026) 251–276 Contents lists available at ScienceDirect Journal of Advanced Research journal [homepage: www. elsevier. com/locate/jare](homepage: www. elsevier. com/locate/jare) Review Article Neddylation: from regulatory mechanisms to clinical implications in cancer Ming Zhang a, 1, Peng Qiu a, 1, Yunxiang Feng a, Tao Yang b, Wei Yao c, Zhengdong Deng d,⁎, Jianming Wang a,⁎ a Department of Biliary and Pancreatic Surgery, Cancer Research Center Afﬁliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei Province, China b Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 Hubei, China c Department of Oncology Afﬁliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei Province, China d Department of Pediatric Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei Province, China | h i g h l i g h t s
• Neddylation governs protein function and cellular processes.
• Focus on cullin family substrates and their diverse functions.
• Examines neddylation’s role across cancer hallmarks.
• Evaluates NAE inhibitors from mechanisms to therapy. | | g r a p h i c a l a b s t r a c t
| | | --- | --- | --- | --- | | a r t i c l e i n f o | | | a b s t r a c t | | Article history:
Received 8 July 2025
Revised 15 October 2025
Accepted 7 November 2025
Available online 12 November 2025 | | | Background: 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.
Aim of review: 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.
Key scientiﬁc concepts of review: 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.
© 2025 The Author(s). Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). | | Keywords: Neddylation
Cullin-RING ligases Cancer hallmarks Precision oncology Therapeutic targeting | | | | ⁎ Corresponding authors. E-mail addresses: [dengzhengdong0915@163.com](dengzhengdong0915@163.com) (Z. Deng), wjm18jgm@aliyun. com (J. Wang). 1 These authors contributed equally to this work. [https://doi.org/10.1016/j.jare.2025.11.010](https://doi.org/10.1016/j.jare.2025.11.010) 2090-1232/© 2025 The Author(s). Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).

FAQs

What is the main focus of the review on neddylation?

The review systematically explains how neddylation and its regulatory mechanisms work, how they promote malignant progression through multiple cancer hallmarks, and how drugs targeting neddylation components are progressing clinically.

Why is neddylation considered important in cancer biology?

Neddylation is frequently hyperactivated in cancers and regulates protein stability, cellular signaling, and core biological processes. Its dysregulation contributes directly to tumorigenesis and progression.

Which therapeutic strategy does the review emphasize?

It evaluates targeted therapeutic approaches against the neddylation pathway and discusses clinical potential, future directions, and toxicity challenges for inhibitors including MLN4924 and TAS4464.

Sep 23, 2026

Uploaded by moss~