{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Stomatology, General Hospital of Northern Theater Command",
    "Department of Urology, The First Affiliated Hospital of Dalian Medical University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xin Tian"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinghan Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Dequan Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Ying Min"
    },
    {
      "affs": [
        0
      ],
      "name": "Yang Hu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9hey1b2frj9ks.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1936781",
  "fulltext_url": null,
  "id": "9hey1b2frj9ks",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1936781/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-29",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/9hey1b2frj9ks.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1936781",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1936781/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:1663-9812",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Targeting neddylation in cancer: molecular mechanisms, translational advances, and therapeutic challenges",
  "title_text": "Targeting neddylation in cancer: molecular mechanisms, translational advances, and therapeutic challenges",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T00:21:07Z",
  "url": "https://research.draconitic.com/paper/9hey1b2frj9ks",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}