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

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.