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 revolutionise 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 recognised as a key driver in tumour 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 tumours to thrive, leading to cell cycle arrest, apoptosis, and reduced tumour progression.

Beyond pharmacological interventions, understanding the role of neddylation in liver cancer has opened doors to personalised 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.

Wu W, Wang X, Ma R, Huang S, Li H, Lyu X. Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics. Genes Dis. 2024 Dec 6;12(4):101483. doi: 10.1016/j.gendis.2024.101483