Funct Integr Genomics. 2026 Jun 19;26(1):150. doi: 10.1007/s10142-026-01917-w.
ABSTRACT
Smoking is a major modifiable risk factor for myocardial infarction (MI); however, the molecular mechanisms through which its core component nicotine and its primary metabolite cotinine mediate MI development remain incompletely understood. This study aimed to identify key molecular targets and characterize the mechanistic basis by which nicotine and cotinine mediate myocardial injury relevant to MI. To this end, we performed two-sample Mendelian randomization using GWAS data for smoking (468,170 participants) and MI (20,197 cases, 440,906 controls) from the IEU Open GWAS Project to genetically validate the smoking-MI causal association. Potential targets of nicotine and cotinine were predicted from four databases (SEA, TargetNET, SwissTargetPrediction, ChEMBL). MI-related targets were retrieved from DisGeNET and GeneCards. Shared targets among nicotine, cotinine, and MI were identified, followed by PPI network analysis, GO/KEGG enrichment, and topological screening (MCC and Degree). Core targets were validated using GEO transcriptomic datasets (GSE113871, GSE115031). Molecular docking and 200-ns molecular dynamics simulations were performed to evaluate potential ligand-target interactions. In vitro CCK-8 and qRT-PCR assays in H9c2 cardiomyocytes assessed cytotoxicity and target expression. MR analysis confirmed a significant positive causal association between smoking and MI. We identified 44 shared targets, with ADRA2A validated as the key functional target. Molecular docking suggested that nicotine and cotinine may potentially bind to ADRA2A, with calculated affinities of - 7.2 and - 6.8 kcal/mol, respectively. MD simulations indicated that the complexes might remain stable during the simulation trajectory. Nicotine and cotinine exerted cytotoxicity in H9c2 cells and significantly upregulated Adra2a mRNA. Collectively, these findings suggest that ADRA2A is a potential critical molecular target mediating nicotine- and cotinine-induced MI, providing novel mechanistic insights and potential therapeutic targets for smoking-related cardiovascular diseases.
PMID:42319523 | DOI:10.1007/s10142-026-01917-w