Deoxynivalenol (DON) is a common contamination mycotoxin that which exerts significant hepatotoxicity, posing a serious threat to human and animal health. Ferroptosis has been linked to the development of hepatotoxicity induced by DON. However, the mechanism by which DON promotes ferroptosis in hepatocytes is not well understood. Although studies have shown that DON upregulates the expression of nicotinamide N-Methyltransferase (NNMT), its role in DON hepatotoxicity has not been elucidated. In this study, we found that DON inhibited SLC7A11/GPX4 and increased cytosolic free Fe^2 + and lipid ROS, thereby inducing ferroptosis of HepG2 cells. Overexpression of NNMT markedly downregulated the expression of SLC7A11, GPX4, GCLC, and NQO1, exacerbated the DON-induced increase in free Fe²⁺ and lipid ROS, thus promoting ferroptosis. Silencing or inhibition of NNMT produced opposite effects and abolished the DON-induced ferroptosis. Further application of SLC7A11 and GPX4 inhibitor treatments confirmed that following DON exposure, NNMT triggered ferroptosis by inhibiting SLC7A11 and GPX4, to reduce cell viability and inhibit cell growth. Taken together, this study found that DON-induced NNMT may enhance ferroptosis by inhibiting the SLC7A11/GPX4 proteins in HepG2 cells. These findings provide valuable insights for controlling DON hepatotoxicity and hepatocellular carcinoma.

01 Mar 2025·Journal of Human Genetics

Genetic inhibition of nicotinamide N-methyltransferase and prevention of alcohol-associated fatty liver in humans

Article

Author: Tian, Zijian ; Pan, Ying ; Weng, Xiong ; Liu, Yiying ; Wu, Benrui ; Zhou, Kaixin ; Shao, Jian ; Wu, Peng ; Xu, Tao ; Huang, Rong

Recent studies of animal models reported Nicotinamide N-methyltransferase (NNMT) as a potential therapeutic target for preventing alcohol-associated fatty liver (AFL), yet its efficacy and safety in humans remain unknown. We aim to estimate the effectiveness and safety of inhibiting NNMT in humans. We leveraged Electronic Medical Records (EMRs) data coupled with genetic information to perform a retrospective drug target validation study. We examined longitudinal clinical data from 612 individuals with excessive alcohol consumption. Two variants lowering NNMT protein levels were combined to calculate a weighted NNMT genetic score that could mimic mild inhibition of NNMT. Participants with an NNMT score above the median were classified as genetically inhibited, while others were considered non-inhibited. We then evaluated whether genetic inhibition of NNMT would affect the incidence of AFL or the risk of liver injury, to illuminate the effectiveness and safety of genetic inhibition of NNMT respectively. NNMT genetic inhibition correlated with a reduced AFL risk (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.49-0.90, P = 0.009) without a significant increase in serum aminotransferase levels (P > 0.10). Notably, elevated ALT and AST levels were observed (P < 0.05) in the genetically inhibited group prior to alcohol exposure. These findings suggest NNMT inhibition is a promising avenue for AFL prevention among individuals with excessive alcohol intake. They also underscore the need for precise target population identification to mitigate potential adverse effects.

01 Feb 2025·Journal of Diabetes and its Complications

Nicotinamide n-methyltransferase inhibitor synergizes with sodium-glucose cotransporter 2 inhibitor to protect renal tubular epithelium in experimental models of type 2 diabetes mellitus

Article

Author: Zhang, Nong ; Li, Yankun ; Li, Fengxia ; Yang, Yuling ; Li, Hui ; Zhao, Zhonghua ; Li, Xue

AIMSWe aim to explore the potential of nicotinamide n-methyltransferase (NNMT) as a sensitive marker of renal tubular injury and the possibility of an NNMT inhibitor to combine with sodium-glucose cotransporter 2 (SGLT2) inhibitor to protect proximal tubular epithelium in vivo and in vitro model of Type 2 diabetes mellitus (T2DM), respectively.METHODSIn vivo, immunohistochemical staining, Masson's trichrome staining and Sirius red staining were used to observe the changes of NNMT expression, renal tubular injury and interstitial fibrosis in renal tissue from the db/db mice. Bioinformatic analysis was also conducted to broaden the range of data validation. In vitro, Western Blot and quantitative RT-PCR were used to measure the degree of damage of HK-2 cells.RESULTSOur in vivo data showed upregulation of NNMT expression paralleled renal tubular damage and interstitial fibrosis. Our in vitro data revealed both NNMT inhibitors and SGLT2 inhibitors can protect against the injury as assessed by extracellular matrix (ECM) synthesis and profibrotic phenotype transition of HK-2 cells, and the combination of these two agents can further reduce these injuries.CONCLUSIONSThe present study is the first to show that NNMT is a promising marker of renal tubular injury in diabetic nephropathy (DN) and NNMT inhibitors can synergize with SGLT2 inhibitors to protect HK-2 better. Our findings will provide the insight and pave the way of developing novel therapeutic strategies for chronic renal tubular injury associated with T2DM.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	Sweden	Sprint Bioscience AB	04 Oct 2024

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