Targeting neddylation in cancer: molecular mechanisms, translational advances, and therapeutic challenges
- 1Department of Stomatology, General Hospital of Northern Theater Command
- 2Department of Urology, The First Affiliated Hospital of Dalian Medical University
Abstract
Neddylation is a ubiquitin-like post-translational modification that regulates cullin–RING ligases and selected non-cullin substrates involved in cell-cycle progression, DNA replication licensing, DNA-damage repair, apoptosis, hypoxic signaling, inflammatory responses, epithelial–mesenchymal transition, metabolic adaptation, and immune regulation. Many tumors rely on aberrant neddylation-dependent protein turnover to sustain proliferation, survival, metastatic plasticity, and therapeutic resistance, making this pathway a compelling anticancer target. This review outlines the molecular architecture of the NEDD8 cascade, encompassing NEDD8 activation, E2-mediated conjugation, E3/co-E3-facilitated ligation, deneddylation, and the central role of cullin–RING ligases as oncogenic effectors. It also examines the principal classes of neddylation-pathway inhibitors, including the first-in-class NEDD8-activating enzyme inhibitor MLN4924, newer NAE inhibitors such as TAS4464, emerging UBE2M- and UBE2F-directed approaches, DCN1/DCUN1-targeted inhibitors, and natural product-derived or other experimental compounds. Preclinical evidence across hematologic malignancies, gastrointestinal and genitourinary cancers, thoracic and head-and-neck tumors, brain tumors, and pediatric cancers indicates that neddylation inhibition can suppress tumor growth and enhance responses to chemotherapy, radiotherapy, apoptosis-targeted agents, proteasome inhibition, autophagy modulation, and immunotherapy. Nevertheless, clinical translation remains constrained by inadequate patient selection, context-dependent substrate accumulation, adaptive resistance, complex immune effects, and limited therapeutic windows. Future development should therefore move beyond empirical pan-pathway inhibition toward biomarker-guided, tumor-context-specific precision strategies integrating selective E1, E2, and E3 inhibitors, rational combination regimens, pharmacodynamic monitoring, resistance profiling, immune-state assessment, and tumor-targeted delivery systems.
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BibTeX
@article{tian2026targeting,
title = {{Targeting neddylation in cancer: molecular mechanisms, translational advances, and therapeutic challenges}},
author = {Xin Tian and Xinghan Li and Dequan Liu and Ying Min and Yang Hu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1936781},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1936781/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting neddylation in cancer: molecular mechanisms, translational advances, and therapeutic challenges
AU - Xin Tian
AU - Xinghan Li
AU - Dequan Liu
AU - Ying Min
AU - Yang Hu
PY - 2026
DA - 2026/10/29
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1936781
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1936781/full
AB - Neddylation is a ubiquitin-like post-translational modification that regulates cullin–RING ligases and selected non-cullin substrates involved in cell-cycle progression, DNA replication licensing, DNA-damage repair, apoptosis, hypoxic signaling, inflammatory responses, epithelial–mesenchymal transition, metabolic adaptation, and immune regulation. Many tumors rely on aberrant neddylation-dependent protein turnover to sustain proliferation, survival, metastatic plasticity, and therapeutic resistance, making this pathway a compelling anticancer target. This review outlines the molecular architecture of the NEDD8 cascade, encompassing NEDD8 activation, E2-mediated conjugation, E3/co-E3-facilitated ligation, deneddylation, and the central role of cullin–RING ligases as oncogenic effectors. It also examines the principal classes of neddylation-pathway inhibitors, including the first-in-class NEDD8-activating enzyme inhibitor MLN4924, newer NAE inhibitors such as TAS4464, emerging UBE2M- and UBE2F-directed approaches, DCN1/DCUN1-targeted inhibitors, and natural product-derived or other experimental compounds. Preclinical evidence across hematologic malignancies, gastrointestinal and genitourinary cancers, thoracic and head-and-neck tumors, brain tumors, and pediatric cancers indicates that neddylation inhibition can suppress tumor growth and enhance responses to chemotherapy, radiotherapy, apoptosis-targeted agents, proteasome inhibition, autophagy modulation, and immunotherapy. Nevertheless, clinical translation remains constrained by inadequate patient selection, context-dependent substrate accumulation, adaptive resistance, complex immune effects, and limited therapeutic windows. Future development should therefore move beyond empirical pan-pathway inhibition toward biomarker-guided, tumor-context-specific precision strategies integrating selective E1, E2, and E3 inhibitors, rational combination regimens, pharmacodynamic monitoring, resistance profiling, immune-state assessment, and tumor-targeted delivery systems.
SN - 1663-9812
ER -