Integrated network pharmacology and Mendelian randomization analysis to elucidate potential mechanisms of curcumin and resveratrol in myocardial infarction treatment

Myocardial infarction (MI) is a major global health burden with limited restorative therapies. Natural compounds such as curcumin and resveratrol offer potential as adjunctive treatments. To elucidate their molecular targets and mechanisms in MI using integrated network pharmacology and summary-data-based Mendelian randomization (SMR). Potential targets of curcumin, resveratrol, and MI-related genes were retrieved from multiple databases. SMR and colocalization analyses using genome-wide association study (FinnGen R12, Million Veteran Program) and expression/protein quantitative trait loci (eQTLGen, Fenland, UK Biobank Pharma Proteomics Project, and deCODE), inferred causal links between target gene/protein expression and MI risk. Protein-protein interaction networks were analyzed for hub genes and drug-target-disease networks were constructed. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Molecular docking assessed compound-target binding. SMR analyses with subsequent validation in Million Veteran Program cohort identified 47 core targets associated with MI and potentially modulated by curcumin and/or resveratrol, exhibiting robust, genetically supported causal associations with MI risk. Further SMR, colocalization, and validation pinpointed key genes such as fibronectin 1 (FN1) and RELA (nuclear factor-κB p65 subunit) with strong MI risk associations and modulation by both compounds. Protein-protein interaction analysis identified FN1, RELA, poly(ADP-ribose) polymerase 1, Sirtuin 1, and tumor protein p53 as hub genes. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment revealed involvement in inflammation, apoptosis, oxidative stress, and key signaling pathways such as phosphatidylinositol 3-kinase/Akt signaling pathway and adenosine monophosphate-activated protein kinase. Molecular docking confirmed strong curcumin/resveratrol binding to FN1 and RELA. Curcumin and resveratrol demonstrate therapeutic potential in MI by modulating a network of targets, prominently FN1 and RELA. These actions converge on crucial protective mechanisms such as reducing inflammation and oxidative stress, providing a basis for developing novel adjunctive MI therapies. SIGNIFICANCE STATEMENT: This study identifies 47 genetically supported targets linking curcumin and resveratrol to reduced myocardial infarction risk, with fibronectin 1 and RELA emerging as key modulators. By integrating network pharmacology, summary-data-based Mendelian randomization, colocalization, and molecular docking, it reveals how these natural compounds may attenuate inflammation, oxidative stress, and cell survival pathways (eg, PI3K-Akt, AMPK), supporting their potential as adjunctive therapies to improve myocardial infarction outcomes.