Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to pose a significant global health challenge due to its high mortality rate and limited treatment options. However, a new frontier in cancer therapy has emerged, focusing on neddylation modification, a crucial cellular process that influences cancer progression. The latest insights into this mechanism provide hope for targeted therapies that could revolutionize the treatment landscape for HCC.
Neddylation is a post-translational modification process in which the NEDD8 protein attaches to cellular substrates, altering their function. This process is now recognized as a key driver in tumor cell proliferation, migration, and survival. Abnormal activation of neddylation has been directly linked to poor prognosis in HCC patients, making it a compelling target for drug development.
The therapeutic potential of neddylation inhibitors is now being explored, with promising results. Agents such as MLN4924 (pevonedistat) and TAS4464 have demonstrated significant efficacy in disrupting cancer cell growth by selectively inhibiting the neddylation pathway. These inhibitors work by interfering with the cellular mechanisms that allow tumors to thrive, leading to cell cycle arrest, apoptosis, and reduced tumor progression.
Beyond pharmacological interventions, understanding the role of neddylation in liver cancer has opened doors to personalized medicine approaches. Identifying biomarkers associated with neddylation dysregulation may enable early detection of HCC, improving patient outcomes through timely and precise treatment strategies.
As research advances, neddylation-targeted therapies are paving the way for novel combination treatments. By integrating these inhibitors with immunotherapies, chemotherapy, and molecular-targeted drugs, clinicians may achieve superior therapeutic responses, especially in patients with advanced-stage HCC.
This review underscores the need for continued exploration into molecular mechanisms driving liver cancer. The future of oncology is moving toward treatments that not only prolong survival but also enhance quality of life. By harnessing the power of neddylation-targeted drugs, the fight against HCC is entering a new era.

Funding Information:
Natural Science Foundation of Shandong Province, China ZR2021QC030
Natural Science Foundation of Shandong Province, China ZR2022LZL006
Innovation Project of Shandong First Medical University

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Reference
Wenxin Wu, Xuanyi Wang, Ruijie Ma, Shuhong Huang, Hongguang Li, Xinxing Lyu, Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics, Genes & Diseases, volume 12, issue 4, 2025, 101483, https://doi.org/10.1016/j.gendis.2024.101483