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Nicotinamide N-Methyltransferase (NNMT) and Liver Cancer: From Metabolic Networks to Therapeutic Targets
Shi-Yan Lai1, Xiao-Juan Zhu1, Wei-Dong Sun1
1Physical Education College, Jiangxi Normal University, Nanchang 330022, China.
Abstract:
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a global health challenge with limited therapeutic options and high mortality rates. Despite advances in understanding its molecular pathogenesis, the role of metabolic reprogramming in HCC progression and therapy resistance demands further exploration. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme central to NAD+ and methionine cycles, has emerged as a critical regulator of tumorigenesis across cancers. However, its tissue-specific mechanisms in HCC-particularly in the context of viral hepatitis and methionine cycle dependency-remain understudied. This review systematically synthesizes current evidence on NNMT's dual role in HCC: (1) driving NAD+ depletion and homocysteine (Hcy) accumulation via metabolic dysregulation, (2) promoting malignant phenotypes (proliferation, invasion, metastasis, and drug resistance), and (3) serving as a prognostic biomarker and therapeutic target. We highlight how NNMT intersects with epigenetic modifications, immune evasion, and metabolic vulnerabilities unique to HCC. Additionally, we critically evaluate NNMT inhibitors, RNA-based therapies, and non-pharmacological strategies (e.g., exercise) as novel interventions. By bridging gaps between NNMT's molecular mechanisms and clinical relevance, this review provides a roadmap for advancing NNMT-targeted therapies and underscores the urgency of addressing challenges in biomarker validation, inhibitor specificity, and translational efficacy. Our work positions NNMT not only as a metabolic linchpin in HCC but also as a promising candidate for precision oncology.
Insights
Nicotinamide N-methyltransferase (NNMT) drives hepatocellular carcinoma (HCC) progression by disrupting metabolic cycles and promoting malignant traits. Targeting NNMT offers a promising strategy for novel HCC therapies.
Area of Science:
- Oncology
- Metabolic pathways
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) presents significant global health challenges due to limited treatment options and high mortality.
- Metabolic reprogramming is increasingly recognized as a key driver of HCC progression and therapeutic resistance.
- Nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD+ and methionine metabolism, is implicated in various cancers but its specific role in HCC requires further elucidation.
Purpose of the Study:
- To systematically review the multifaceted role of NNMT in hepatocellular carcinoma (HCC).
- To explore NNMT's impact on metabolic dysregulation, malignant phenotypes, and therapeutic resistance in HCC.
- To evaluate NNMT as a prognostic biomarker and potential therapeutic target for HCC.
Main Methods:
- Systematic literature review and synthesis of current evidence on NNMT in HCC.
- Analysis of NNMT's involvement in NAD+ depletion and homocysteine accumulation.
- Evaluation of NNMT's intersection with epigenetic modifications, immune evasion, and metabolic vulnerabilities in HCC.
Main Results:
- NNMT contributes to HCC pathogenesis by depleting NAD+ and increasing homocysteine levels.
- NNMT promotes HCC cell proliferation, invasion, metastasis, and resistance to therapies.
- NNMT is identified as a prognostic biomarker and a potential therapeutic target in HCC.
Conclusions:
- NNMT plays a critical, dual role in HCC progression and therapeutic resistance through metabolic reprogramming.
- Targeting NNMT via inhibitors, RNA-based therapies, or lifestyle interventions presents novel therapeutic avenues for HCC.
- Further research is needed to validate NNMT biomarkers and optimize NNMT-targeted therapies for clinical efficacy in HCC precision oncology.
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