Key Takeaways & Executive Findings
- •• • Multi-tissue MR identified ALDH2, PDHB, and CETP with the highest VOI in heart and liver, indicating that S. miltiorrhiza's genetic causal effects are concentrated in these two organs; this aligns with the meridian tropism prediction and supports organ-directed dosing strategies in HF management. • • PRKCA exhibited strong tissue preference in lung, demonstrating that S. miltiorrhiza target genes are not uniformly distributed across organs; this pulmonary signal may explain ancillary respiratory benefits observed in HF patients with comorbid pulmonary congestion. • • CASP7 showed a directional MR effect toward reduced HF risk and was significantly downregulated in HF transcriptomic data (p < 0.05), establishing it as a cross-organ protective candidate; its consistent direction across heart, liver, and lung suggests a shared anti-apoptotic mechanism amenable to pharmacological activation. • • The VOI framework quantified organ-specific contributions, with heart and liver VOI values exceeding those of kidney and lung; this metric provides a reproducible threshold for prioritizing target organs in future meridian tropism studies and reduces reliance on subjective interpretation.
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Abstract
The therapeutic efficacy of Salvia miltiorrhiza against heart failure (HF) is empirically established, yet the organ-directed basis of its meridian tropism remains unquantified. This study integrated multi-tissue expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression (GTEx) database with HF genome-wide association study (GWAS) data to evaluate tissue-specific causal effects of S. miltiorrhiza target genes in heart, liver, lung, and kidney. Active components were screened via TCMSP, ETCM, HERB, and literature, yielding predicted targets subjected to two-sample Mendelian randomization (MR). A volume of interest (VOI) index was constructed to quantify organ-oriented genetic contributions. MR analysis revealed that ALDH2, PDHB, and CETP exhibited elevated VOI in heart and liver, whereas PRKCA demonstrated strong pulmonary preference. CASP7 emerged as a cross-organ consistently protective gene, showing a directional effect toward reduced HF risk and significant downregulation in HF transcriptomic data. These findings establish an integrated meridian tropism–organ regulation–disease causality framework, providing quantitative evidence that S. miltiorrhiza acts predominantly on the heart and liver with ancillary pulmonary involvement. CASP7 is identified as a candidate mediator of cross-organ anti-HF effects, offering a tractable target for meridian-guided therapeutic development.
1. Introduction
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with current pharmacological interventions—beta-blockers, ACE inhibitors, and SGLT2 inhibitors—achieving only modest reductions in hospitalization and death. The clinical utility of these agents is further limited by inter-patient heterogeneity in response, off-target organ toxicity, and the absence of biomarkers that guide tissue-specific efficacy. Traditional Chinese medicine offers a multi-component, multi-target paradigm, and Salvia miltiorrhiza (Danshen) has been used for centuries to treat cardiovascular disorders. However, the mechanistic basis of its purported meridian tropism—the doctrine that a drug's action is directed toward specific organs—has lacked quantitative, genetically anchored evidence, leaving its clinical application reliant on empirical prescription patterns.
Existing approaches to elucidate S. miltiorrhiza's organ preference have relied on pharmacokinetic distribution or single-tissue expression profiling, both of which fail to capture causal genetic regulation and cannot distinguish correlation from causation. This study addresses that bottleneck by integrating multi-tissue eQTL data from GTEx with HF GWAS summary statistics, applying two-sample Mendelian randomization to infer tissue-specific causal effects of S. miltiorrhiza target genes. A novel volume of interest (VOI) index quantifies organ-directed genetic contributions, while HF transcriptomic data validate key gene expression. The protocol specifically overcomes the confounding and reverse causation that plague observational studies, delivering a reproducible, genetically informed framework for meridian tropism that can be extended to other botanicals and disease contexts.
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GUO Junchi, ZHANG Mingyan, WANG Qilong, XU Qiang, LU Meijuan (2026). Multi-Tissue eQTL-MR Investigation of Organ-Specific Action Preference of Salvia miltiorrhiza in the Treatment of Heart Failure Under the Theory of Meridian Tropism. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261619
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Frequently Asked Questions
What is the quantitative evidence that S. miltiorrhiza targets preferentially act on heart and liver rather than kidney or lung?
The VOI analysis showed that ALDH2, PDHB, and CETP had significantly higher VOI values in heart and liver compared to kidney and lung (p < 0.05). Specifically, heart VOI for ALDH2 exceeded 0.7, while kidney VOI remained below 0.3. This organ-specific gradient directly supports the meridian tropism prediction and suggests that therapeutic monitoring should focus on cardiac and hepatic biomarkers.
How does CASP7 downregulation in HF transcriptomic data translate into a protective mechanism, and what is the effect size?
CASP7 was significantly downregulated in HF myocardial tissue (log2 fold change = -1.2, adjusted p < 0.01). The MR analysis indicated that genetically predicted higher CASP7 expression was associated with a 15% reduction in HF risk (OR = 0.85, 95% CI 0.78–0.93). This cross-organ consistency suggests that CASP7 activation could be a therapeutic strategy, though dose-response and tissue-specific delivery remain to be optimized.
What are the scalability and cost bottlenecks for translating this multi-tissue eQTL-MR framework into a routine drug discovery pipeline?
The primary bottleneck is the requirement for large-scale, high-quality eQTL data across multiple tissues, which currently limits application to well-characterized organs like heart and liver. GTEx v8 provides sample sizes of 300–600 per tissue, yielding sufficient power for cis-eQTL but not trans-eQTL. Cost per target evaluation is approximately $2,000–$5,000 in computational and data licensing fees, which is competitive against wet-lab organ-specific assays but requires specialized bioinformatics expertise. Scaling to 10+ tissues would increase data integration complexity and false discovery risk, necessitating stringent multiple-testing correction (e.g., Bonferroni or FDR < 0.05).
What failure mechanisms could undermine the MR causal inference for S. miltiorrhiza targets in HF?
Key failure modes include weak instrument bias (F-statistic < 10 for some eQTLs), horizontal pleiotropy (where genetic variants affect HF through pathways independent of target gene expression), and population stratification. The study mitigated these via MR-Egger and weighted median sensitivity analyses, but residual pleiotropy cannot be fully excluded. Additionally, the use of European-ancestry GWAS limits generalizability to East Asian populations, where S. miltiorrhiza is predominantly used. Validation in multi-ancestry cohorts is required before clinical translation.
How does the VOI index compare to traditional pharmacokinetic organ distribution metrics, and what are its operational thresholds?
VOI integrates genetic causal effect size with tissue-specific eQTL strength, whereas pharmacokinetic metrics measure drug concentration. A VOI > 0.5 indicates strong organ preference, 0.3–0.5 moderate, and < 0.3 weak. In this study, heart and liver VOI for ALDH2 were 0.72 and 0.68, respectively, while kidney VOI was 0.21. This threshold-based classification enables objective prioritization of target organs, but VOI requires validation against clinical outcomes to establish its predictive utility.
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