目的 基于中医“归经理论”，从遗传调控、因果推断及转录组学等多层证据出发，系统解析丹参治疗心力衰竭的器官作用偏好及其关键分子机制。方法 通过TCMSP、ETCM、HERB及文献资料筛选丹参主要活性成分，并预测潜在靶基因。随后整合基因型-组织表达（genotype-tissue expression，GTEx）数据库的多组织表达数量性状位点（expression quantitative trait loci，eQTL）与心力衰竭全基因组关联研究（genome-wide association study，GWAS）数据，采用两样本孟德尔随机化（Mendelian randomization，MR）评估靶基因在心脏、肝脏、肺组织及肾组织中的组织特异性因果效应，并构建器官作用偏好指数（volume of interest，VOI）量化其器官定向特征，结合心力衰竭转录组数据分析关键基因的表达特征。结果 多组织MR显示，丹参靶基因在心脏、肝脏及肺组织中均呈现一定的遗传效应特征。VOI分析提示乙醛脱氢酶2（aldehyde dehydrogenase 2，ALDH2）、丙酮酸脱氢酶E1β亚基（pyruvate dehydrogenase E1 beta subunit，PDHB）、胆固醇酯转移蛋白（cholesteryl ester transfer protein，CETP）等靶基因在心脏和肝脏中贡献较高，而蛋白激酶Cα（protein kinase C alpha，PRKCA）等靶基因在肺组织中亦表现出较强的组织偏好。跨器官一致受保护的关键基因半胱氨酸蛋白酶-7（Caspase-7，CASP7）在MR分析中表现为降低心力衰竭风险的方向性效应，且在心力衰竭转录组中显著下调。结论 构建了“归经-器官调控-疾病因果效应”一体化分析框架。丹参相关靶基因表现出以心、肝为主并涉及肺组织的多器官作用特征，为丹参传统归经理论提供了新的量化研究线索且提出CASP7可能是其发挥跨器官抗心力衰竭作用的重要候选靶点。

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.

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国家自然科学基金面上项目（82374195）；国家自然科学基金面上项目（82374619）；天津市卫健委中医中西医结合科研课题（2023027）