Objective Based on the traditional Chinese medicine (TCM) theory of meridian tropism, this study aimed to systematically elucidate the organ-specific therapeutic preference of Salvia miltiorrhiza in heart failure (HF) and its key molecular mechanisms by integrating multi-level evidence from genetic regulation, causal inference, and transcriptomics. Methods Major active components of S. miltiorrhiza were screened through TCMSP, ETCM, HERB, and document literature, and potential target genes were predicted. Genotype-tissue expression (GTEx) multi-tissue expression quantitative trait loci (eQTL) data and heart failure genome-wide association study (GWAS) data were then integrated, and a two-sample Mendelian randomization (MR) framework was applied to evaluate the tissue-specific causal effects of target genes in the heart, liver, lung, and kidney. The volume of interest (VOI) was further constructed to quantify organ-oriented characteristics, and HF transcriptomic data were used to analyze the expression patterns of key genes. Results Multi-tissue MR showed that S. miltiorrhiza target genes exhibited certain genetic effect patterns in the heart, liver, and lung. VOI analysis indicated that genes such as aldehyde dehydrogenase 2 (ALDH2), pyruvate dehydrogenase E1 beta subunit (PDHB), and cholesteryl ester transfer protein (CETP) contributed more prominently in the heart and liver, whereas genes such as protein kinase C alpha (PRKCA) also showed relatively strong tissue preference in the lung. The cross-organ consistently protective key gene Caspase-7 (CASP7) showed a directional effect associated with reduced HF risk in MR analysis and was significantly downregulated in HF transcriptomic data. Conclusion This study established an integrated framework linking meridian tropism, organ regulation, and disease-related causal effects. The results suggest that S. miltiorrhiza-related target genes exhibit a multi-organ action pattern dominated by the heart and liver while also involving lung tissue, providing new quantitative clues for the traditional meridian tropism theory of S. miltiorrhiza and suggesting that CASP7 may be an important candidate target mediating its cross-organ anti-HF effects.

Salvia miltiorrhiza Bge.  /  heart failure  /  meridian tropism  /  Mendelian randomization  /  organ-specific action preference