Potential Therapeutic Targets for the Treatment of Atrial Fibrillation via Lipid Regulation and Inflammatory Mechanisms: A Comprehensive Analysis of Multiple Methods on Triangular Herbal Combination S-N-C

Introduction: The incidence of atrial fibrillation (AF) is rising, leading to increased use of traditional Chinese medicine (TCM) such as Salvia miltiorrhiza Bge. (Dans-hen), Nardostachys jatamansi DC. (Gansong), and Citrus medica L. var. sarcodactylis Swingle (Foshou) (abbreviated S-N-C) triangular herbal combination for early intervention. However, the mechanisms behind its effects are unclear. This study aims to explore the mechanisms of the anti-AF effects of the S-N-C combination. Methods: An integrative strategy incorporating network pharmacology, Mendelian randomization (MR), and other related analytical approaches was applied to elucidate the potential therapeutic mechanisms of the S-N-C in AF treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) class II analysis was conducted on the intersection genes to identify pivotal pathways implicated in the treatment of AF. These important pathways were subsequently screened to further Drug-target MR analysis. Additional methods included gene expression, PheWAS, molecular docking, and molecular dynamics (MD) simulations. Results: Network pharmacology identified 294 S-N-C targets in AF. KEGG analysis highlighted lipid-modulating effects through lipid and atherosclerosis pathways. Drug-target MR and colocalization analyses indicated S-N-C targets Glycogen Synthase Kinase 3 Beta (GSK3B) to regulate lipid metabolism. KEGG class II analysis, as well as literature, indicated that Phosphoinositide 3-Kinase/Akt(PI3K-Akt), Mitogen-Activated Protein Kinase (MAPK), and Tumor Necrosis Factor(TNF) pathways were involved in inflammatory response. Inflammatory protein MR Analysis confirmed inflammatory gene overlap and mapped a PPI network with Caspase 8(CASP8) as a key node. Gene expression was highest in blood; PheWAS suggested safety. Molecular docking and MD simulations revealed stable binding interactions between S-N-C components and GSK3B/CASP8. Discussion: This study elucidates that the S-N-C herbal combination exerts therapeutic effects against atrial fibrillation primarily through multi-target mechanisms involving GSK3B-mediated lipid metabolism regulation and CASP8-associated inflammatory pathways. By integrating network pharmacology with Mendelian randomization, we provide mechanistic evidence supporting the traditional use of this formula. The findings highlight the potential of targeting lipid-inflammatory crosstalk in AF management and demonstrate how systems pharmacology approaches can bridge traditional medicine with modern precision therapeutics. Conclusions: S-N-C may treat AF by modulating lipid pathways via GSK3B and inflammation via CASP8 and related proteins.