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The role of nicotinamide in improving cardiac function suggests its therapeutic benefit for acute myocardial infarction (AMI). This study aims to identify key genes associated with nicotinamide metabolism in AMI, offering novel insights into its therapeutic management. The GSE60993 and GSE61144 datasets were retrieved from the database. Mendelian randomization (MR) analysis, Cytoscape-plugin cytoHubba algorithms, and expression validation were used to identify key genes linked to nicotinamide metabolism. Subcellular localization, gene set enrichment analysis (GSEA), immune infiltration analysis, drug prediction, and molecular docking were then performed. Finally, the expression of key genes was validated experimentally in clinical samples. Three key genes (FLT3LG, ITGB7, and PARP1) were found to be causally associated with AMI, ranking in the top three of the three Cytoscape-plugin cytoHubba algorithms. FLT3LG and ITGB7 were identified as risk factors (odds ratio [OR] > 1, P-value < 0.05), while PARP1 was a protective factor (OR < 1, P-value < 0.05). Expression analysis in GSE60993 and GSE61144 confirmed similar trends for these genes. FLT3LG and ITGB7 were predominantly located in the cytoplasm, whereas PARP1 was mainly in the nucleus. GSEA results indicated involvement of these genes in pathways such as the ribosome, oxidative phosphorylation, and spliceosome. Immune infiltration analysis showed that neutrophil scores were higher in AMI and negatively correlated with ITGB7 (cor = -0.84), PARP1 (cor = -0.75), and FLT3LG (cor = -0.86). Drug prediction and molecular docking revealed strong correlations between the key genes and Tetradioxin, with excellent binding ability. Expression trends of the three genes in clinical samples aligned with bioinformatics findings. This study identified three genes associated with nicotinamide metabolism whose altered expression or function may have played a role in the pathological process of AMI. These genes could provide potential reference points for the diagnosis and treatment of AMI.