NNMT(Sprint Bioscience)

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.

We 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.

In 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.

Our 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.

The 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.