1 Introduction

Ischemic heart disease (IHD), has a relatively high incidence and mortality rate worldwide, accounting for nearly one-third of global deaths. Coronary heart disease, as the most common type of IHD, accounts for approximately 40% of cardiovascular-related deaths. Its risk factors includes diabetes, hypertension, dyslipidemia, obesity and unhealthy lifestyles, which have led to an increasing incidence rate in both developed, and developing countries (Zhang et al., 2023). Myocardial ischemia (MI), is characterized by an imbalance between oxygen supply and demand in the myocardium, which in turn leads to damage and death of myocardial cells. The key pathological mechanisms include oxidative stress, inflammatory response, endothelial dysfunction, apoptosis and metabolic disorders. These factors jointly drive myocardial infarction, fibrosis and poor cardiac remodeling (Zhou et al., 2012; Lin et al., 2021; Zhang et al., 2023).

In traditional Chinese Medicine (TCM), Salvia miltiorrhiza (Danshen) has been used to treat cardiovascular diseases for hundreds of years, including angina pectoris, myocardial infarction and heart failure. Its root extract is renowned for promoting blood circulation, and removing blood stasis, improving blood circulation and relieving chest pain (Zhang et al., 2023; Shan et al., 2024). Modern pharmacological research has found that, the active ingredients contained in S. miltiorrhiza, like tanshinone and tanshinic acid, have antioxidant, anti-inflammatory, endothelial protective, anti-apoptotic and anti-fibrotic effects.

Experimental and clinical studies have further demonstrated that, Salvia miltiorrhiza extract can reduce infarction area, improve cardiac function, regulate metabolism and inflammatory pathways, and has a protective effect on myocardial ischemia-reperfusion injury (Ren et al., 2019; Lin et al., 2021; Shan et al., 2024; Li et al., 2025). These effects are achieved through multi-target mechanisms, such as regulating oxidative stress, lipid metabolism, angiogenesis, and signaling pathways, like PI3K/Akt, NF-κB, and TGF-β/Smad (Zhang et al., 2023; Cai et al., 2024; Mu et al., 2024).

This study attempts to clarify the multi-target protective mechanism of Salvia miltiorrhiza extract in an experimental model of ischemic heart disease, with a focus on exploring its role in regulating oxidative stress, inflammation, apoptosis, metabolism and cardiac remodeling. By revealing the molecular and cytological effects of Salvia miltiorrhiza, we strive to provide new insights and scientific basis for the prevention and treatment of ischemic heart disease, and promote the integration of traditional medicine and modern pharmacology.

2 Bioactive Constituents of S. miltiorrhiza Extracts

2.1 Lipophilic components

The main liposoluble components of S. miltiorrhiza are tanshinones, a class of compounds with a shell-taxane-type diterpene quinone structure, contains tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone. These compounds mainly exist in the root, and are one of the core substances of the pharmacological activity of S. miltiorrhiza, especially playing an important role in cardiovascular protection (Li et al., 2018; Jiang et al., 2019; Ren et al., 2019; Ye et al., 2023). Among them, tanshinone IIA is the most abundant and has been studied the most deeply. It has been proven to play an important role in clinical and experimental cardiovascular treatment. The biosynthesis of tanshinone involves a complex cytochrome P450 enzyme network, and its content is affected by genetic and environmental factors (Lu, 2021; Li et al., 2021; 2024).

Tanshinoone has antioxidant activity, can eliminate reactive oxygen species (ROS), and enhance endogenous antioxidant defense in the body, reducing oxidative stress in ischemic tissues (Jiang et al., 2019). Tanshinone also has anti-apoptotic effects. It can protect cardiomyocytes from ischemia-induced cell death by regulating signaling pathways, such as PI3K/Akt and Nrf2, and inhibiting inflammatory mediators (Li et al., 2018; Ye et al., 2023). These effects help reduce myocardial damage and improve cardiac function in ischemic heart disease models.

2.2 Hydrophilic components

The main water-soluble components of Salvia miltiorrhiza are phenolic acids, mainly including salvianolic acid B, salvianolic acid A, rosmarinic acid and salvia miltiorrhiza (Wei et al., 2023; Mu et al., 2024). Among them, salvianolic acid B is the most abundant, and has the strongest biological activity. Due to its antioxidant and anti-inflammatory effects, it has received more attention (Li et al., 2018; Ren et al., 2019). These phenolic acid components are soluble in water, and exist in the roots and aboveground parts of Salvia miltiorrhiza (Wu et al., 2016; Shi et al., 2018; Hou et al., 2020).

Phenolic acid compounds in S. miltiorrhiza are potent free radical scavengers, and can protect vascular endothelial cells and myocardial cells from oxidative damage (Li et al., 2018; Wei et al., 2023; Mu et al., 2024). They can activate antioxidant pathways, like Nrf2/HO-1, inhibit lipid peroxidation, reduce inflammatory damage, and thereby alleviate ischemic injury. Genetic engineering studies have shown that, by enhancing the biosynthesis of phenolic acids, antioxidant activity can be increased in engineered Salvia miltiorrhiza plants (Fu et al., 2020; Zhou et al., 2021).

2.3 Synergistic actions of constituents

The liposoluble tanshinones and water-soluble phenolic acids in S. miltiorrhiza act on different, but complementary molecular targets. Tanshinoone mainly regulates oxidative stress, apoptosis and inflammatory response, while phenolic acids have outstanding advantages in free radical scavenging and vascular endothelial protection (Li et al., 2018; Wei et al., 2023; Ye et al., 2023). The combined application of the two, can jointly act on multiple signaling pathways, such as PI3K/Akt, Nrf2, MAPKs and TGF-β/Smad, enhancing the overall therapeutic effect (Ren et al., 2019; Mu et al., 2024).

The synergistic effect among these components enhances the overall cardioprotective effect of S. miltiorrhiza extract. The interaction of its multiple components can improve blood circulation, reduce infarction area, and better maintain cardiac function in ischemic heart disease models (Wei et al., 2023; Mu et al., 2024; Qian et al., 2025). The latest research indicates that, the combined application of tanshinone I and salfanolic acid A, can exhibit a synergistic effect on vascular normalization, and tissue protection in ischemic models. This multi-target and multi-pathway mode of action is precisely the basis for S. miltiorrhiza to play a role in traditional medicine and modern cardiovascular treatment (Ye et al., 2023).

3 Pathophysiology of Myocardial Ischemic Injury and the Regulatory Role

3.1 Oxidative stress and cellular damage under S. miltiorrhiza intervention

Myocardial ischemia leads to excessive reactive oxygen species (ROS) production and mitochondrial dysfunction, resulting in oxidative damage and cell death. Tanshinones, key lipophilic components of S. miltiorrhiza, have been shown to attenuate ROS generation, preserve mitochondrial integrity, and reduce oxidative injury in ischemic heart models, thereby protecting cardiomyocytes from ischemia-reperfusion damage (Huang et al., 2023; Zhong et al., 2023).

Hydrophilic constituents, like salvianolic acid B, exert potent antioxidant effects by scavenging free radicals and activating the Nrf2 signaling pathway, which upregulates endogenous antioxidant defenses (Hu et al., 2019; Tao et al., 2019; Shen et al., 2022). This reduces lipid peroxidation, ferroptosis, and apoptosis in cardiomyocytes following ischemic injury.

3.2 Inflammation and apoptosis modulated by S. miltiorrhiza

S. miltiorrhiza extract can inhibit the activation of the NF-κB pathway, and down-regulate the levels of pro-inflammatory cytokines, like TNF-α, IL-1β and IL-6, thereby alleviating the inflammatory response after myocardial ischemia (Duan et al., 2023; Huang et al., 2023; Shan et al., 2024). This anti-inflammatory effect is mainly mediated through the TLR4/NF-κB and NLRP3 inflammasome pathways.

Meanwhile, S. miltiorrhiza reduces the apoptotic level of cardiomyocytes, by activating survival signaling pathways (e.g., Akt/ERK1/2/Nrf2, JAK2/STAT3), and inhibiting pro-apoptotic factors, thereby increasing the survival rate of myocardium after ischemic injury (Huang et al., 2023; Zhong et al., 2024).

3.3 Hemodynamic dysfunction and endothelial injury improved by S. miltiorrhiza

Ischemic injury can weaken endothelial function and vasodilation ability. S. miltiorrhiza improves vasodilation and restores endothelial function, by enhancing endothelial nitric oxide synthase (eNOS) activity, and increasing nitric oxide (NO) production, which is crucial for maintaining myocardial perfusion (Huang et al., 2023; Wu et al., 2024). S. miltiorrhiza and its active ingredients also can promote angiogenesis, protect microvascular integrity, and improve microcirculation disorders in ischemic myocardium. This process is partially achieved by up-regulating VEGF and related pathways (Zhang et al., 2023).

4 Cardioprotective Effects of Salvia miltiorrhiza

4.1 Antioxidant and free radical scavenging effects

S. miltiorrhiza extract and its active components, like tanshinone and salvianate, can significantly enhance the activity of endogenous antioxidant enzymes in myocardial tissue, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). In animal models and clinical studies, this upregulation effect has been consistently observed, thereby improving the clearance ability of reactive oxygen species (ROS), and protecting cardiomyocytes from oxidative damage during ischemia (Chang et al., 2016; Ren et al., 2019; Li et al., 2025).

S. miltiorrhiza treatment can also reduce the generation of lipid peroxidation products, such as malondialdehyde (MDA) and thiobarbituric acid reactants (TBARS), which are important markers of oxidative membrane damage. This effect effectively maintains the integrity of myocardial cell membranes, and limits the injury range caused by ischemia (Cheng et al., 2021). The inhibition of lipid peroxidation is closely related to the upregulation of antioxidant enzyme activity, and the direct free radical scavenging effect of S. miltiorrhiza components.

4.2 Anti-inflammatory and anti-apoptotic effects

S. miltiorrhiza and its active components, especially tanshinone IIA and salvianolic acids, can inhibit the activation of the NF-κB signaling pathway, and down-regulate the expression of pro-inflammatory cytokines, like TNF-α, IL-1β and IL-6. This anti-inflammatory effect has been verified in both in vitro and in vivo models of myocardial ischemia, manifested as a reduction in inflammatory cell infiltration and tissue damage (Ren et al., 2019; Wei et al., 2023; Wu et al., 2024). As Li et al. (2025) found, the active components of S. miltiorrhiza, such as tanshenone and tanshenic acid, exert anti-fibrotic effects through multiple mechanisms, containing inhibiting ventricular remodeling, regulating autophagy, promoting extracellular matrix degradation, anti-inflammation, inhibiting oxidative stress and cardiomyocyte apoptosis (Figure 1).

Besides, S. miltiorrhiza extract regulates the apoptotic pathway by increasing the expression of anti-apoptotic protein Bcl-2 and reducing the level of pro-apoptotic protein Bax, thereby reducing cardiomyocyte apoptosis and improving cell survival rate after ischemic injury (Guo et al., 2020; Hung et al., 2020; Jung et al., 2020; Zhang et al., 2023). This cytoprotective mechanism achieved by regulating the Bcl-2/Bax ratio is an important link for S. miltiorrhiza to exert cytoprotective effects in ischemic myocardium.

4.3 Improvement of hemodynamics

S. miltiorrhiza can enhance the activity of endothelial nitric oxide synthase (eNOS), and the production of nitric oxide (NO), promote vasodilation and improve vascular function. This effect is crucial for restoring blood flow to ischemic myocardium, and has been confirmed by preclinical and clinical studies (Chang et al., 2016; Wang et al., 2017; Luo et al., 2023; Zhang et al., 2025).

By improving endothelial function and microcirculation, S. miltiorrhiza can increase coronary blood flow and myocardial perfusion, which helps maintain cardiac function, and reduce infarction area in ischemic heart disease models (Mu et al., 2017; Ren et al., 2019; Cheng et al., 2021). This hemodynamic improvement is also associated with better recovery of left ventricular function, and a slower progression of heart failure.

5 Molecular Pathway Mechanisms of Salvia miltiorrhiza

5.1 PI3K/Akt pathway

S. miltiorrhiza and its active components, like tanshinone and salvianolic acids, can significantly activate the PI3K/Akt pathway, which is a core regulatory axis for cell survival and cardiac protection. Network pharmacology and experimental studies have identified AKT1 as a key target. Pathway enrichment analysis further confirmed that, PI3K/Akt is an important pathway for S. miltiorrhiza to exert its effect (Liu et al., 2023; Wei et al., 2023; Hou et al., 2025). The activation of Akt, can promote the phosphorylation of downstream effector molecules, thereby enhancing cell survival, improving metabolic adaptation, and supporting tissue repair in ischemic heart models (Zhang et al., 2021).

Through PI3K/Akt signaling, S. miltiorrhiza can up-regulate the expression of anti-apoptotic proteins (like Bcl-2) and down-regulate pro-apoptotic factors (Bax), thereby inhibiting cardiomyocyte apoptosis, reducing ischemia-induced cell death and improving cardiac function (Liu et al., 2023). This anti-apoptotic effect is one of the key mechanisms, by which Salvia miltiorrhiza exerts its protective effect on the heart.

5.2 Nrf2/HO-1 pathway

The components of S. miltiorrhiza can promote the nuclear translocation of Nrf2. Nrf2, as the core transcription factor of antioxidant defense, can bind to the antioxidant response element (AREs) in the genome after activation, and up-regulate the expression of antioxidant enzymes, like HO-1, SOD and CAT (Meng et al., 2022; Fu et al., 2023; Wei et al., 2023). This mechanism enhances the cells' defense ability against oxidative stress, which is an important factor in myocardial ischemic injury.

HO-1 induced by Nrf2 activation, plays a dual role in antioxidation and anti-inflammation. It enhances the overall cardioprotective effect of S. miltiorrhiza, by degrading pro-oxidative hemoglobin, generating molecules with cytoprotective effects, such as bilivermin and carbon monoxide, and inhibiting inflammatory responses (Meng et al., 2022; Fu et al., 2023). Studies have shown that, polysaccharides and phenolic acid components in S. miltiorrhiza can activate the Nrf2/HO-1 pathway, thereby reducing ferroptosis and oxidative damage, and exhibit significant protective effects in cardiac and vascular models.

5.3 MAPK and TLR4 pathways

S. miltiorrhiza can regulate the MAPK pathway, containing ERK, JNK and p38, influencing cell survival, apoptosis and stress response. By regulating the MAPK signal, S. miltiorrhiza helps balance pro-survival and pro-apoptotic signals, thereby further protecting cardiomyocytes in ischemic injury (Wei et al., 2023; Hou et al., 2025). KEGG pathway analysis and experimental data indicate that, MAPK1 and MAPK14 are one of the core targets of S. miltiorrhiza (Zhang et al., 2021).

In addition, S. miltiorrhiza also can inhibit the TLR4-mediated signaling pathway, which is a key link in the inflammatory response of ischemic injury. By down-regulating TLR4 and its downstream effector molecules (like NF-κB), S. miltiorrhiza reduces cytokine production and inflammatory cell infiltration, thereby alleviating myocardial injury (Meng et al., 2022; Wei et al., 2023). The TLR4/MyD88/NF-κB axis is a common target of salvianolic acid and tanshinone, which provides a molecular basis for the anti-inflammatory and anti-apoptotic effects, exhibited by S. miltiorrhiza in cardiovascular models.

6 Experimental Evidence of Salvia miltiorrhiza Extracts

6.1 Cell-based studies

Cell models of hypoxia/reoxygenation (H/R) injury, have been widely used to simulate in vitro ischemic heart disease studies. Studies have shown that extracts of S. miltiorrhiza, especially tanshinone IIA and salvianolic acid B, can significantly reduce myocardial cell death, maintain mitochondrial function, and enhance cell survival under oxidative stress conditions. These effects are attributed to the upregulation of antioxidant enzymes, the reduction of ROS, and the regulation of survival pathways such as PI3K/Akt and Nrf2/HO-1 (Ren et al., 2019; Jung et al., 2020; Mu et al., 2024).

In vitro experiments have shown that, the extract of S. miltiorrhiza can inhibit the expression of pro-inflammatory cytokines, like TNF-α, IL-1β, and apoptotic markers (Bax, caspase-3, etc.), while increasing the level of anti-apoptotic proteins (such as Bcl-2). These results were verified by western blot, ELISA and qPCR analyses, supporting the anti-inflammatory and anti-apoptotic properties of S. miltiorrhiza extract in cardiomyocyte models (Ren et al., 2019; Jung et al., 2020).

In antioxidant experiments at the cellular level, S. miltiorrhiza extract can reduce intracellular ROS and malondialdehyde (MDA) levels, while enhancing the activities of superoxide dismutase (SOD) and catalase (CAT). These results further confirm that, S. miltiorrhiza extract has a strong free radical scavenging and antioxidant capacity in protecting cardiomyocytes from oxidative damage (Jiang et al., 2019; Mu et al., 2024).

6.2 Animal model studies

In myocardial ischemia/reperfusion (I/R) injury models of rats and mice, administration of S. miltiorrhiza extract can improve cardiac function, reduce infarction area, and restore hemodynamic parameters to normal. Whether it was the water extract, ethanol extract, or isolated monomer components, like tanshinoone IIA and salvianolic acid B, they all showed cardioprotective effects in these models (Zhou et al., 2012; Ren et al., 2019; Jung et al., 2020). Animal studies also established dose-dependent relationships, that is, the cardioprotective effects of tanshinone IIA and salvianolic acid B increased with dose, manifested as improved cardiac function, increased antioxidant enzyme activity and reduced tissue damage, and no significant toxicity was observed at the therapeutic level.

Long-term animal experiments on administration have shown that, S. miltiorrhiza extract can continuously improve cardiac prognosis and demonstrates good safety. No obvious adverse reactions or organ toxicity were found at the therapeutic dose, providing support for its long-term application in cardiovascular diseases.

6.3 Mechanistic validation experiments

Institutional studies confirmed through Western blotting and qPCR that, S. miltiorrhiza extract can activate the PI3K/Akt and Nrf2/HO-1 pathways, and regulate the MAPK signaling pathway. These molecular changes are closely related to enhanced antioxidation, reduced inflammation and improved cell survival, and have been verified in cell and animal models (Ren et al., 2019; Jung et al., 2020; Mu et al., 2024).

Gene knockout and inhibitor experiments further verified the role of the related pathways. For instance, in the Nrf2−/− or TLR4−/− models, the protective effect of S. miltiorrhiza was weakened, confirming the specificity of these molecular targets in their cardioprotective effects (Jiang et al., 2019; Jung et al., 2020). Multi-omics studies, including metabolomics and network pharmacology, have identified key active ingredients and their molecular targets, providing evidence for understanding the systemic cardioprotective mechanism of S. miltiorrhiza (Ren et al., 2019; Mu et al., 2024). Metabolomics analysis reveals that, the aqueous extract of S. miltiorrhiza mainly exerts cardioprotective effects, by regulating metabolic pathways, such as histidine, alanine, aspartic acid and glutamic acid, glycerophospholipids, as well as glycine, serine and threonine (Figure 2).

7 Case Studies

7.1 Cardiovascular protective effect of Salvianolic acid B

The water-soluble phenolic acid component - salvianolic acid B in S. miltiorrhiza has powerful anti-inflammatory and antioxidant effects. It can inhibit the expression of pro-inflammatory cytokines, like TNF-α, IL-6, reduce the generation of ROS, and protect cells from lipid peroxidation damage, effectively alleviating myocardial injury in cell and animal models (Huang et al., 2016; Li et al., 2023; Shan et al., 2024).

Salvianolic acid B also can maintain endothelial integrity, and promote vasodilation, improving coronary blood flow and microcirculation. Studies show that, it can enhance angiogenesis and reduce endothelial dysfunction, improve myocardial perfusion and reduce ischemic injury (Lin et al., 2021; Li et al., 2023; Zhang et al., 2023).

7.2 The efficacy and mechanism of A. membranaceus and S. miltiorrhiza combination on MI

Myocardial ischemia (MI) is one of the leading cardiovascular diseases, which causing death and disability worldwide. Despite the development of various treatment methods in modern medicine, there are still limitations, especially in terms of myocardial reperfusion, and long-term cardiac function recovery. Traditional Chinese medicine (TCM) has a long history in the treatment of cardiovascular diseases. Many plant medicinal materials have been found to have the effects of promoting angiogenesis and protecting the heart (Hung, 2019; Lin et al., 2021; Zhang et al., 2023).

Zhang et al. (2023) explored the therapeutic effect and mechanism of the TCM combination "A. membranaceus and S. miltiorrhiza (AS)" on myocardial ischemia (MI). The study used a mouse model of MI, induced by ligation of the left anterior descending coronary artery (LAD), and found that AS could reduce MI area, improve cardiac function, including restoring abnormal electrocardiogram, increasing ejection fraction and shortening fraction, and reducing the levels of heart failure markers BNP and NT-proBNP. Histological analysis shows that, AS can also alleviate myocardial pathological damage, such as reducing infarction area, myocardial remodeling and fibrosis. Importantly, the research mechanism reveals that, AS promotes angiogenesis by facilitating pericytes recruitment and upregulating factors, like vascular endothelial cadherin, VEGF, and TGF-β. Its mode of action is related to the Ang-1/Tie-2/FAK signaling pathway (Figure 3). These findings indicate that AS is expected to become a novel adjuvant therapy for myocardial ischemia, and has broad application prospects.

8 Conclusions and Perspectives

S. miltiorrhiza extract has demonstrated multi-target cardioprotective effects, in ischemic heart disease models, and its mechanisms involve antioxidant, anti-inflammatory, anti-apoptotic and endothelial protection aspects. The lipophilic components, like tanshinones, and water-soluble components (e.g., salvianolic acids) in S. miltiorrhiza work in synergy to regulate multiple molecular pathways, including PI3K/Akt, Nrf2/HO-1, MAPK, etc. The integration results of these molecular mechanisms are manifested as the improvement of cardiac function, the reduction of infarct area, and the alleviation of myocardial remodeling and fibrosis. S. miltiorrhiza can also regulate the metabolic profile, intestinal microbiota and angiogenesis, further supporting its therapeutic potential in ischemic heart disease.

Although preclinical studies and some clinical evidence are encouraging, there is still a lack of large-scale, well-designed clinical trials to comprehensively verify the efficacy and safety of S. miltiorrhiza extract in different patient groups. Most of the existing data are derived from animal models or small-scale clinical studies, which limits their value in transformation and application. Meanwhile, the active components in S. miltiorrhiza are complex, with over 200 compounds identified. The synergistic or antagonistic effects among them have not been fully clarified, and further mechanism research is urgently needed.

Future research should rely more on multi-omics techniques (metabolomics, proteomics, single-cell analysis, etc.), to reveal the spatiotemporal dynamics of the active components and their targets of S. miltiorrhiza, thereby clarifying the molecular basis of its cardioprotective effects. Based on this, it is expected that new types of S. miltiorrhiza derived drugs and optimized preparations will be developed, including improved or compound extracts, to enhance efficacy and safety. Continuous interdisciplinary research and clinical validation will be the key to transforming these findings into novel treatment approaches for ischemic heart disease.

Acknowledgments

The authors sincerely thank Ms. Zhang for her valuable assistance during the research and writing of this manuscript. The authors also extend heartfelt gratitude to the two anonymous reviewers whose comments and suggestions greatly contributed to the improvement of the manuscript.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Cai K., Zhang W., Su S., Yan H., Liu H., Zhu Y., Shang E., Guo S., Liu F., and Duan J., 2024, Salvia miltiorrhiza stem-leaf of total phenolic acid conversion products alleviate myocardial ischemia by regulating metabolic profiles, intestinal microbiota and metabolites, Biomedicine and Pharmacotherapy, 177: 117055.

https://doi.org/10.1016/j.biopha.2024.117055

Chang C.C., Chang Y.C., Hu W.L., and Hung Y.C., 2016, Oxidative stress and Salvia miltiorrhiza in aging-associated cardiovascular diseases, Oxidative Medicine and Cellular Longevity, 2016(1): 4797102.

https://doi.org/10.1155/2016/4797102

Cheng Y.C., Hung I.L., Liao Y.N., Hu W.L., and Hung Y.C., 2021, Salvia miltiorrhiza protects endothelial dysfunction against mitochondrial oxidative stress, Life, 11(11): 1257.

https://doi.org/10.3390/life11111257

Duan S., Zhang M., Zeng H., Song J., Zhang M., Gao S., Yang H., Ding M., and Li P., 2023, Integrated proteomics and phosphoproteomics profiling reveals the cardioprotective mechanism of bioactive compounds derived from Salvia miltiorrhiza Burge, Phytomedicine, 117: 154897.

https://doi.org/10.1016/j.phymed.2023.154897

Fu R., Shi M., Deng C., Zhang Y., Zhang X., Wang Y., and Kai G., 2020, Improved phenolic acid content and bioactivities of Salvia miltiorrhiza hairy roots by genetic manipulation of RAS and CYP98A14, Food Chemistry, 331: 127365.

https://doi.org/10.1016/j.foodchem.2020.127365

Fu Y., Peng X., Zhang C., Jiang Q., Li C., Paulsen B., Rise F., Huang C., Feng B., Li L., Chen X., Jia R., Li Y., Zhao X., Ye G., Tang H., Liang X., Lv C., Tian M., Yin Z., and Zou Y., 2023, Salvia miltiorrhiza polysaccharide and its related metabolite 5-methoxyindole-3-carboxaldehyde ameliorate experimental colitis by regulating Nrf2/Keap1 signaling pathway, Carbohydrate Polymers, 306: 120626.

https://doi.org/10.1016/j.carbpol.2023.120626

Guo R., Li L., Su J., Li S., Duncan S.E., Liu Z., and Fan G., 2020, Pharmacological activity and mechanism of tanshinone IIA in related diseases, Drug Design, Development and Therapy, 14: 4735-4748.

https://doi.org/10.2147/DDDT.S266911

Hou M., Hu W., Hao K., Xiu Z., Zhang X., and Liu S., 2020, Enhancing the potential exploitation of Salvia miltiorrhiza Bunge: Extraction, enrichment and HPLC-DAD analysis of bioactive phenolics from its leaves, Industrial Crops and Products, 158: 113019.

https://doi.org/10.1016/j.indcrop.2020.113019

Hou S., Fan Z., Wang X., Li K., Ding H., Wang X., Li Y., and Gao X., 2025, Study on the mechanism of Salvia miltiorrhiza in the treatment of prostatic hyperplasia based on online pharmacology, Asia Pacific Journal of Clinical Medical Research, 1(1).

https://doi.org/10.62177/apjcmr.v1i1.335

Hu Y., Li Q., Pan Y., and Xu L., 2019, Sal B alleviates myocardial ischemic injury by inhibiting TLR4 and the priming phase of NLRP3 inflammasome, Molecules, 24(23): 4416.

https://doi.org/10.3390/molecules24234416

Huang W., Yang Y., Zeng Z., Su M., Gao Q., and Zhu B., 2016, Effect of Salvia miltiorrhiza and ligustrazine injection on myocardial ischemia/reperfusion and hypoxia/reoxygenation injury, Molecular Medicine Reports, 14(5): 4537-4544.

https://doi.org/10.3892/mmr.2016.5822

Huang X., Zhang M., Song Y., Sun B., Lin L., Song X., and Li C., 2023, Integrated network pharmacology to investigate the mechanism of Salvia miltiorrhiza Bunge in the treatment of myocardial infarction, Journal of Cellular and Molecular Medicine, 27(22): 3514-3525.

https://doi.org/10.1111/jcmm.17932

Hung Y.C., Wang P.W., Lin T.Y., Yang P.M., You J.S., and Pan T.L., 2020, Functional redox proteomics reveal that Salvia miltiorrhiza aqueous extract alleviates adriamycin-induced cardiomyopathy via inhibiting ROS-dependent apoptosis, Oxidative Medicine and Cellular Longevity, 2020(1): 5136934.

https://doi.org/10.1155/2020/5136934

Jiang Z., Gao W., and Huang L., 2019, Tanshinones, critical pharmacological components in Salvia miltiorrhiza, Frontiers in Pharmacology, 10: 202.

https://doi.org/10.3389/fphar.2019.00202

Jung I., Kim H., Moon S., Lee H., and Kim B., 2020, Overview of Salvia miltiorrhiza as a potential therapeutic agent for various diseases: an update on efficacy and mechanisms of action, Antioxidants, 9(9): 857.

https://doi.org/10.3390/antiox9090857

Li B., Li J., Chai Y., Huang Y., Li L., Wang D., and Wang Z., 2021, Targeted mutagenesis of CYP76AK2 and CYP76AK3 in Salvia miltiorrhiza reveals their roles in tanshinones biosynthetic pathway, International Journal of Biological Macromolecules, 189: 455-463.

https://doi.org/10.1016/j.ijbiomac.2021.08.112

Li H., Jiang X., Mashiguchi K., Yamaguchi S., and Lu S., 2024, Biosynthesis and signal transduction of plant growth regulators and their effects on bioactive compound production in Salvia miltiorrhiza (Danshen), Chinese Medicine, 19(1): 102.

https://doi.org/10.1186/s13020-024-00971-5

Li Q., Ren C., Jiang B., Wang X., Wang C., Zhi X., Li L., Guo X., Zhao X., and Li Y., 2025, Salvia miltiorrhiza Bunge root in the treatment of myocardial fibrosis: research progress and challenges, Frontiers in Pharmacology, 16: 1554696.

https://doi.org/10.3389/fphar.2025.1554696

Li X., Liu R., Liu W., Liu X., Fan Z., Cui J., Wu Y., Yin H., and Lin Q., 2023, Panax quinquefolium L. and Salvia miltiorrhiza Bunge enhances angiogenesis by regulating the miR-155-5p/HIF-1α/VEGF axis in acute myocardial infarction, Drug Design, Development and Therapy, 17: 3249-3267.

https://doi.org/10.2147/DDDT.S426345

Li Z.M., Xu S.W., and Liu P.Q., 2018, Salvia miltiorrhiza Burge (Danshen): a golden herbal medicine in cardiovascular therapeutics, Acta Pharmacologica Sinica, 39(5): 802-824.

https://doi.org/10.1038/aps.2017.193

Lin R., Mu F., Li Y., Duan J., Zhao M., Guan Y., Liu K., Bai Y., Wen A., Wei P., Wang J., and Xi M., 2021, Salvia miltiorrhiza and the volatile of Dalbergia odorifera attenuate chronic myocardial ischemia injury in a pig model: a metabonomic approach for the mechanism study, Oxidative Medicine and Cellular Longevity, 2021(1): 8840896.

https://doi.org/10.1155/2021/8840896

Liu Y., Huang J., Sujie L., Chen Y., Yang Z., Wang J., and Zhao T., 2023, To explore the mechanism of Salvia miltiorrhiza in preventing liver fibrosis based on angiogenesis, Medical Research Frontiers, 2(4): 189.

https://doi.org/10.57237/j.mrf.2023.04.006

Lu S., 2021, Biosynthesis and regulatory mechanisms of bioactive compounds in Salvia miltiorrhiza, a model system for medicinal plant biology, Critical Reviews in Plant Sciences, 40(3): 243-283.

https://doi.org/10.1080/07352689.2021.1935719

Luo L., Xue J., Shao Z., Zhou Z., Tang W., Liu J., Hu H., and Yang F., 2023, Recent developments in Salvia miltiorrhiza polysaccharides: isolation, purification, structural characteristics and biological activities, Frontiers in Pharmacology, 14: 1139201.

https://doi.org/10.3389/fphar.2023.1139201

Meng H., Wu J., Shen L., Chen G., Jin L., Yan M., Wan H., and He Y., 2022, Microwave assisted extraction, characterization of a polysaccharide from Salvia miltiorrhiza Bunge and its antioxidant effects via ferroptosis-mediated activation of the Nrf2/HO-1 pathway, International Journal of Biological Macromolecules, 215: 398-412.

https://doi.org/10.1016/j.ijbiomac.2022.06.064

Mu F., Duan J., Bian H., Yin Y., Zhu Y., Wei G., Guan Y., Wang Y., Guo C., Wen A., Yang Y., and Xi M., 2017, Cardioprotective effects and mechanism of Radix Salvia miltiorrhiza and Lignum Dalbergiae odoriferae on rat myocardial ischemia/reperfusion injury, Molecular Medicine Reports, 16(2): 1759-1770.

https://doi.org/10.3892/mmr.2017.6821

Mu X., Yu H., Li H., Feng L., Ta N., Ling L., Bai L., A.R., Borjigidai A., Pan Y., and Fu M., 2024, Metabolomics analysis reveals the effects of Salvia miltiorrhiza Bunge extract on ameliorating acute myocardial ischemia in rats induced by isoproterenol, Heliyon, 10(9): e30488.

https://doi.org/10.1016/j.heliyon.2024.e30488

Qian C., Huang Y., Zhang S., Yang C., Zheng W., Tang W., Wan G., Wang A., Lu Y., and Zhao Y., 2025, Integrated identification and mechanism exploration of bioactive ingredients from Salvia miltiorrhiza to induce vascular normalization, Phytomedicine, 138: 156427.

https://doi.org/10.1016/j.phymed.2025.156427

Ren J., Fu L., Nile S.H., Zhang J., and Kai G., 2019, Salvia miltiorrhiza in treating cardiovascular diseases: a review on its pharmacological and clinical applications, Frontiers in Pharmacology, 10: 753.

https://doi.org/10.3389/fphar.2019.00753

Shan X., Li J., Hong B., Yin H., Lu Z., Wang G., Yu N., Peng D., Wang L., Zhang C., and Chen W., 2024, Comparative efficacy of sweated and non-sweated Salvia miltiorrhiza Bge. extracts on acute myocardial ischemia via regulating the PPARα/RXRα/NF-κB signaling pathway, Heliyon, 10(11): e31923.

https://doi.org/10.1016/j.heliyon.2024.e31923

Shen Y., Shen X., Wang S., Zhang Y., Wang Y., Ding Y., Shen J., Zhao J., Qin H., Xu Y., Zhou Q., Wang X., and Shen J., 2022, Protective effects of salvianolic acid B on rat ferroptosis in myocardial infarction through upregulating the Nrf2 signaling pathway, International Immunopharmacology, 112: 109257.

https://doi.org/10.1016/j.intimp.2022.109257

Shi M., Huang F., Deng C., Wang Y., and Kai G., 2019, Bioactivities, biosynthesis and biotechnological production of phenolic acids in Salvia miltiorrhiza, Critical Reviews in Food Science and Nutrition, 59(6): 953-964.

https://doi.org/10.1080/10408398.2018.1474170

Tao H., Yang X., Wang W., Yue S., Pu Z., Huang Y., Shi X., Chen J., Zhou G., Chen Y., Zhao M., Tang Y., and Duan J., 2019, Regulation of serum lipidomics and amino acid profiles of rats with acute myocardial ischemia by Salvia miltiorrhiza and Panax notoginseng herb pair, Phytomedicine, 67: 153162.

https://doi.org/10.1016/j.phymed.2019.153162

Wang L., Ma R., Liu C., Liu H., Zhu R., Guo S., Tang M., Li Y., Niu J., Fu M., Gao S., and Zhang D., 2017, Salvia miltiorrhiza: a potential red light to the development of cardiovascular diseases, Current Pharmaceutical Design, 23(7): 1077-1097.

https://doi.org/10.2174/1381612822666161010105242

Wei B., Sun C., Wan H., Shou Q., Han B., Sheng M., Li L., and Kai G., 2023, Bioactive components and molecular mechanisms of Salvia miltiorrhiza Bunge in promoting blood circulation to remove blood stasis, Journal of Ethnopharmacology, 317: 116697.

https://doi.org/10.1016/j.jep.2023.116697

Wu C.F., Karioti A., Rohr D., Bilia A.R., and Efferth T., 2016, Production of rosmarinic acid and salvianolic acid B from callus culture of Salvia miltiorrhiza with cytotoxicity towards acute lymphoblastic leukemia cells, Food Chemistry, 201: 292-297.

https://doi.org/10.1016/j.foodchem.2016.01.054

Wu Y., Zhang G., Li L., Liu B., Wang R., Song R., Hua Y., Bi Y., Han X., Zhang F., Wang D., Xie L., and Zhou Y., 2024, Salvia miltiorrhiza suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling, Journal of Ethnopharmacology, 330: 118214.

https://doi.org/10.1016/j.jep.2024.118214

Ye Z., Liu Y., Song J., Gao Y., Fang H., Hu Z., Zhang M., Liao W., Cui L., and Liu Y., 2023, Expanding the therapeutic potential of Salvia miltiorrhiza: a review of its pharmacological applications in musculoskeletal diseases, Frontiers in Pharmacology, 14: 1276038.

https://doi.org/10.3389/fphar.2023.1276038

Zhang L., Han L., Wang X., Wei Y., Zheng J., Zhao L., and Tong X., 2021, Exploring the mechanisms underlying the therapeutic effect of Salvia miltiorrhiza in diabetic nephropathy using network pharmacology and molecular docking, Bioscience Reports, 41(6): BSR20203520.

https://doi.org/10.1042/BSR20203520

Zhang M., Liu Y., Sun X., Zhang X., and Hua L., 2025, Salvia miltiorrhiza adjuvant therapy facilitates cardiac function recovery in patients with myocardial infarction, Pakistan Journal of Pharmaceutical Sciences, 38(1): 45-54.

Zhang M.X., Huang X.Y., Song Y., Xu W.L., Li Y.L., and Li C., 2023, Astragalus propinquus Schischkin and Salvia miltiorrhiza Bunge promote angiogenesis to treat myocardial ischemia via Ang-1/Tie-2/FAK pathway, Frontiers in Pharmacology, 13: 1103557.

https://doi.org/10.3389/fphar.2022.1103557

Zhong L., Dong L., Sun J., Yang J., Yu Z., He P., Zhu B., Zhu Y., Li S., and Xu W., 2024, Network pharmacology and subsequent experimental validation reveal the synergistic myocardial protection mechanism of Salvia miltiorrhiza Bge. and Carthamus tinctorius L., Journal of Traditional Chinese Medical Sciences, 11(1): 44-54.

https://doi.org/10.1016/j.jtcms.2023.11.003

Zhou R., He L.F., Li Y.J., Shen Y., Chao R.B., and Du J.R., 2012, Cardioprotective effect of water and ethanol extract of Salvia miltiorrhiza in an experimental model of myocardial infarction, Journal of Ethnopharmacology, 139(2): 440-446.

https://doi.org/10.1016/j.jep.2011.11.030

Zhou W., Shi M., Deng C., Lu S., Huang F., Wang Y., and Kai G., 2021, The methyl jasmonate-responsive transcription factor SmMYB1 promotes phenolic acid biosynthesis in Salvia miltiorrhiza, Horticulture Research, 8: 443.

https://doi.org/10.1038/s41438-020-00443-5