Nicotinamide N-Methyltransferase (NNMT) and Liver Cancer - From Metabolic Networks to Therapeutic Targets

Sep 23, 2026

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a global health challenge with limited therapeutic options and high mortality rates. Metabolic reprogramming in HCC progression and therapy resistance requires further study. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme central to NAD+ and methionine cycles, regulates tumorigenesis across cancers, yet tissue-specific mechanisms in HCC are insufficiently characterized. This review synthesizes evidence for NNMT’s dual role in HCC, spanning metabolic dysregulation, malignant phenotypes, prognostic value, and therapeutic targeting. It also evaluates inhibitors, RNA-based and non-pharmacological strategies while addressing biomarker and translation challenges.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages25

Reading Time1 h 3 min

AccessFree to download

Abstract

Introduction

Primary liver cancer and challenges

Dual role of NNMT across tumors

NNMT levels, metabolic regulation, and disease links

Review Nicotinamide N-Methyltransferase (NNMT) and Liver Cancer: From Metabolic Networks to Therapeutic Targets Shi-Yan Lai , Xiao-Juan Zhu, Wei-Dong Sun , Shuang-Zhou Bi, Chen-Ying Zhang , An Liu and Jiang-Hua Li * Academic Editor: Jorge Joven Received: 31 March 2025 Revised: 4 May 2025 Accepted: 12 May 2025 Published: 14 May 2025 Citation: Lai, S.-Y.; Zhu, X.-J.; Sun, W.-D.; Bi, S.-Z.; Zhang, C.-Y.; Liu, A.; Li, J.-H. Nicotinamide N-Methyltransferase (NNMT) and Liver Cancer: From Metabolic Networks to Therapeutic Targets. Biomolecules 2025, 15, 719. [https://](https://)[ ](https://)[doi.org/10.3390/biom15050719](doi.org/10.3390/biom15050719) [Copyright:](Copyright:) © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . Physical Education College, Jiangxi Normal University, Nanchang 330022, China; [laishiyan@jxnu.edu.cn](laishiyan@jxnu.edu.cn) (S.-Y.L.); [zhxjhh@jxnu.edu.cn](zhxjhh@jxnu.edu.cn) (X.-J.Z.); [sunweidong0@jxnu.edu.cn](sunweidong0@jxnu.edu.cn) (W.-D.S.); [bishuangzhou@jxnu.edu.cn](bishuangzhou@jxnu.edu.cn) (S.-Z.B.); [18738910347@jxnu.edu.cn](18738910347@jxnu.edu.cn) (C.-Y.Z.); [liuan@jxnu.edu.cn](liuan@jxnu.edu.cn) (A.L.) * Correspondence: [lijianghua8@jxnu.edu.cn](lijianghua8@jxnu.edu.cn) 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 aroadmap 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. Keywords: NNMT; liver cancer; NAD+ metabolism; Hcy level; prognosis; therapeutic targets 1. Introduction Primary liver cancer (PLC) ranks as the sixth most prevalent type of cancer globally and the third major contributor to cancer-related mortality [1] . PLC primarily consists of three types: intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) . HCC constitutes approximately 90% of primary liver cancer cases [2], exhibiting both high incidence and mortality rates [3] . Growing evidence suggests that early stages of HCC development and its precursor lesions share common features regulated by genetic and epigenetic mechanisms [4,5] . Additionally, alterations in various methylation processes have been observed

FAQs

What is the main focus of this review?

The review analyzes how Nicotinamide N-methyltransferase (NNMT) contributes to liver cancer by connecting metabolic network changes with therapeutic opportunities.

How does NNMT influence HCC biology according to the abstract?

NNMT is described as driving NAD+ depletion and homocysteine accumulation, promoting malignant phenotypes such as proliferation, invasion, metastasis, and drug resistance.

Why is NNMT considered both a biomarker and a therapeutic target?

The review states that NNMT can serve as a prognostic biomarker and a candidate therapeutic target, while also highlighting challenges in biomarker validation and inhibitor specificity.

Sep 23, 2026

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