Microvascular angina (MVA) falls under the umbrella of ischemia and non-obstructive coronary artery disease (INOCA) Ang et al. (2022). Nearly 72% of INOCA patients exhibit coronary microvascular dysfunction, among whom 52% specifically present with isolated primary MVA (Al-Mohaissen, 2023). As a type of coronary artery disease (CAD), MVA has manifestations of coronary microvascular dysfunction (CMD) and usually refers to coronary microvascular disease (CMVD) without obstructive coronary artery disease, but its concept may extend further to include patients with obstructive coronary artery disease and after coronary revascularization or heart transplantation (Berry et al., 2022; Abouzid et al., 2024). The potential for major adverse cardiovascular events, like cardiovascular death, is increased by MVA. Besides, MVA is also associated with a poor prognosis and a poor quality of life (Zhong et al., 2020). Patients with CMVD remain under-treated because existing management guidelines do not address this large, mostly female population due to the absence of evidence-based data. Currently, western treatment for patients with CMVD centres on symptom and primary risk factor therapy. Common treatments like beta-blockers, statins, ACEIs/ARBs, and CCBs lack extensive clinical trial data on efficacy and safety (Soleymani et al., 2022). Non-pharmacological treatments, including transcutaneous neurostimulation, and cognitive behavioral therapy, lack strong evidence-based recommendations (Liang et al., 2020). Therefore, it is crucial to focus on preventive and therapeutic approaches that target the underlying disease mechanisms of MVA to reduce associated morbidity and mortality risks.

The advantages of Traditional Chinese Medicine (TCM) in the treatment of MVA have been confirmed by many clinical studies (Yang et al., 2022). However, although TCM is efficacious, it still has serious side effects when used incorrectly (Hou and Jiang, 2013). Foods have less prominent and rapid therapeutic effects, but they have milder side effects, can be taken safely at higher doses, and can be taken for longer periods of time (Hou and Jiang, 2013). Both come from the same source, and there is no absolute boundary between the two. Medicine food homology (MFH) refers to substances traditionally used as food and listed in the Chinese Pharmacopoeia. National Health Commision of the People’s Republic of China has recently announced 110 MFH drugs (Qu et al., 2023). MFH scientifically combines the functions of food and medicine by incorporating nutritional value, healthcare activities, and disease prevention and alleviation (Chien et al., 2015). With the growing global trend towards returning to nature and simplicity, there is a rising demand for MFH not only in China but also worldwide (Qu et al., 2023). The MFH formula (MFHF) can combine the advantages of MFH with TCM compound prescriptions. However, there are no studies on MFH for the treatment of MVA, and the specific mechanism of which is still unclear. These limitations hinder the application of MFH drugs in the prevention and alleviation of MVA. Therefore, it is urgently needed to develop new drugs.

The current study utilized data mining techniques to construct a fundamental formula for the treatment of MVA from MFH drugs. The underlying pharmacodynamic components and possible molecular mechanisms were also explored through the network pharmacology of this MFHF. Simultaneously, the main active ingredients were docked with core targets for preliminary validation.

Data mining is an important tool for discovering relationships and potential associations between massive amounts of data (Liu et al., 2023). Some mining methods have been very successful in studying the combinatorial patterns of traditional Chinese medicines (Liu et al., 2023).

Network pharmacology, a burgeoning field, integrates experimental, clinical, and computational approaches to enhance drug effectiveness (Sadaqat et al., 2023). This innovative trend has found applications across diverse domains, including cardiovascular diseases, paving the way for improved therapeutic outcomes (Sadaqat et al., 2023).

Molecular docking is the utilization of computer technology to simulate the geometric structure and spatial interactions between drug ingredients and disease targets in order to identify ingredients with therapeutic significance.

This strategy provides a new way to fully utilize the existing food and drug resources to promote the development of MVA prevention and symptomatic alleviation.

The overall flow chart of this study is shown in Figure 1.

Patients with MVA caused by CMVD experience major adverse cardiac events Berry et al. (2022). MVA has difficulties in controlling symptoms and a higher rate of subsequent emergency department visits, hospital admissions, or invasive investigations (Aribas et al., 2022). Risk factors for MVA are hypertension, diabetes, insulin resistance, aging, atherosclerosis (AS), hypercholesterolemia, obesity, and others (Herscovici et al., 2018). Studies have shown that coronary microvascular structural or functional dysfunction, inflammatory response, vascular endothelial dysfunction, silent atherosclerosis, and neurological abnormalities with a low threshold for chest pain play important roles in the etiology of the disease (Recio-Mayoral et al., 2013; Berry et al., 2022; Mehta et al., 2022; Soleymani et al., 2022). In coronary microvascular functional dysfunction, the endothelium-dependent and non-endothelium-dependent mechanisms have been demonstrated. Endothelium-dependent mechanisms include impaired vasodilatory responses, vasodilator-vasoconstrictor imbalance (reduced NO release and elevated plasma ET-1 levels, etc.), and an increased contractile response to endothelin and thrombus-mediated contraction. Non-endothelium-dependent mechanisms include the presence of risk factors, estrogen deficiency, and inflammatory response. Structural abnormalities include microvascular remodelling (Soleymani et al., 2022). In addition, there are mechanisms such as increased membrane sodium-hydrogen exchanger activity, platelet aggregation, psychological morbidity, and genetic variants that have been implicated in the development of MVA (Soleymani et al., 2022).

In view of the current lack of efficacy and side effects of western medicines in the treatment of microvascular angina, a core MFH formula was generated in this study, which takes into account the advantages of TCM compound prescription and the food. The MFHF can be widely used as healthcare medicines and healthcare food in our daily lives. It is likely that MFH formula can help people with MVA to relieve anxiety and depression, in the name of “food”.

In Chinese medicine, according to its clinical characteristics of MVA, it is called “true cardiac pain” and “chest bi-impediment/cardiac pain”. “Deficiency of qi and yin” and “intertwined phlegm and blood stasis” are its basic pathogenesis (Zhong et al., 2020). The elements of TCM patterns for MVA in descending order are Blood stasis > Qi deficiency > Turbid phlegm > Qi impediment > Yin deficiency > Pathogenic dampness.

Through data mining, we created a MFHF. The seven constituent drugs of MFHF target the respective pattern element of MVA. Persicae Semen and Angelicae Sinensis Radix circulate blood and transform stasis, Astragali Radix and Codonopsis Radix tonify qi and generate fluid, Platycodonis Radix and Allii Macrostemonis Bulbus circulate qi and transform phlegm, Glycyrrhizae Radix Et Rhizoma relieves spasm and pain, coordinating the rest of ingredients in a formula.

Persicae Semen (PS), also known as Taoren, is the seed of Prunus persica (L.) BATSCH (Rosaceae)(Fukuda et al., 2003). It is commonly used in Asian countries to treat blood stagnation syndromes due to its anticoagulant, antiphlogistic, and anodyne (Xi et al., 2013). MVA patients may have abnormal central autonomic nervous system network (CAN) function. (Cattaneo et al., 2020). PS and its active compounds affect neuron differentiation, which is essential for the CAN to function in the nervous system. Therefore, it is hypothesized that PS regulates CAN by influencing neuron differentiation and serves as a therapeutic agent for MVA. Amygdalin, the active ingredient in PS, can decrease blood viscosity and improve microcirculation to treat CMD associated with MVA (Zhang et al., 2018). Myocardial scarring was prevalent in women with MVA, but PS could prevent scar formation (Xi et al., 2013; Aldiwani et al., 2021). Besides, PS inhibits nuclear factor-kappa B (NF-κB) and tumor necrosis factor-α (TNF-α), which are mediators of endothelial dysfunction (Perrot-Applanat et al., 2011; Xi et al., 2013).

Angelicae Sinensis Radix (ASR), also known as Danggui, is the root of Angelica sinensis (Oliv.) Diels (Apiaceae), widely marketed as a health food and dietary supplement in both Asia and Western countries (Chen et al., 2013). It helps circulate blood, alleviate pain, and tonify qi and blood, exhibiting various pharmacological effects like neuroprotective, immunoregulatory, antioxidant, and hematopoietic activities (Chen et al., 2013).

Astragali Radix (AR), also known as Huangqi, is the root of Angelica sinensis (Oliv.) Diels (Umbelliferae), commonly used to tonify qi and blood, with therapeutic effects on viral and bacterial infections, inflammation, fatigue, and particularly cardiovascular diseases (CVDs) (Chen Z. et al., 2020; Zhang et al., 2020; Li M. et al., 2022). Huangqi extracts, like astragaloside IV, demonstrate strong protective effects against CVDs (Zhang et al., 2020). They can treat AS by inhibiting inflammation, circulating monocytes (MCs) adhesion, lipid disorders, and foam cell formation, exhibiting significant protective effects on vascular endothelial damage (Liu et al., 2022). The mechanism involves diverse pathways, primarily anti-inflammatory and growth factor signaling (Su et al., 2021).

Codonopsis Radix (CR), commonly known as Dangshen, is the root of Codonopsis pilosula (Franch.) Nannf., having effects on tonifying qi, nourishing blood, and promoting bodily fluid production (Luan et al., 2021). The extracts of CR have various pharmacological effects, such as neuroprotection, immune system regulation, anti-tumor properties, endocrine regulation, hypoglycemic effects, improved hematopoietic function, cardiovascular protection, anti-aging, antioxidant, anti-inflammatory, anti-fatigue, and antiviral effects (Dong et al., 2023).

Platycodonis Radix (PR), also known as Jiegeng, is the root of Platycodon grandiflorum (Li Q. et al., 2022). Platycodin D (PD), the main active ingredient, exhibits multiple bioactivities, including analgesic, fat-reducing, insulin resistance improvement, anti-tumor, immune regulation, anti-inflammatory, lipid reduction (Li Q. et al., 2022). PD can prevent infection-induced CMD by blocking the pathway to novel coronavirus infection and exhibits a wide range of pharmacological effects on the cardiovascular system, such as protecting vascular endothelial cells, anti-platelet abnormal activation, anti-atherosclerosis, and so on (Li Q. et al., 2022).

Allii Macrostemonis Bulbus (AMB), also known as Xiebai, bulb of Allium macrosemonis Bulbus and Allium chinense, is considered a “top grade” herb for the treatment of “chest bi-impediment/cardiac pain”, and has the function of activating Yang and removing stasis, circulating qi and resolving stagnation (Yao et al., 2016; Wu et al., 2023). AMB plays a protective role against CVDs. It has various pharmacological activities such as antiplatelet aggregation, hypolipidemic, anti-atherosclerotic, anti-hypertensive, vascular endothelial cell protection, anti-tumor, antispasmodic, antimicrobial, antioxidant, and antidepressant effects (Yao et al., 2016).

Glycyrrhizae Radix et Rhizoma (GRR), also named Gancao and licorice, is the root and rhizome of the Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat., and Glycyrrhizaglabra L (Ding et al., 2022). It has anti-inflammatory, antioxidant, antidiabetic, anti-allergic, antiviral, and immunomodulatory functions, with multiple pharmacological effects on the respiratory, cardiovascular, and immune systems (Li et al., 2020; Ding et al., 2022; Zhang et al., 2024). Besides, GRR may treat AS by inhibiting platelet aggregation, thrombosis and abnormal VSMC proliferation (Liu et al., 2022).

The pharmacological effects of the seven MFH drugs mentioned above form the basis for treating MVA.

Based on the “ingredient-pathway-target” network, five main ingredients (adenosine, nonanoic acid, lauric acid, caprylic acid, and enanthic acid) were identified for their potential roles in preventing and treating MVA by modulating multiple signaling pathways. Adenosine, the main active ingredient in AMB, blocks the synthesis of thromboxane A2 (TXA2) and significantly inhibits platelet aggregation, which causes an alteration in the resting activity of the sodium-hydrogen exchanger in patients with MVA (Applegate and Sane, 2001; Yao et al., 2016). Adenosine possesses analgesic, anti-inflammatory, cardioprotective, antisclerotic, and antifibrotic properties, along with platelet inhibitory and vasodilatory effects (D'Amario et al., 2020). Phosphorylated adenosine forms are involved in cellular energy transfer and regulate various pathologies linked to ischemic heart injury.

Nonanoic acid, lauric acid, caprylic acid, and enanthic acid belong to medium-chain fatty acids (MCFAs), which may play a therapeutic role against MVA by inhibiting platelet aggregation (Takachi et al., 2004). MCFAs also promote fatty acid metabolism, increasing energy production and protecting cardiomyocytes from apoptosis during ischemic heart disease. Estrogen is essential for endothelial integrity and anti-inflammatory properties. MCFAs can help prevent and treat MVA by increasing serum estrogen levels (Zeng et al., 2022). Meanwhile, caprylic acid has potential applications in mitigating oxidative stress, inflammation, apoptosis, stabilizing mitochondria, anti-aging, anti-infective, and improving the circulatory system (Zeng et al., 2022). Overall, MCFAs have potential therapeutic benefits in treating MVA and improving overall health.

Go enrichment analyses reveal that BP primarily involves response to xenobiotic stimulus, CC is related to the integral component of plasma membrane, and MF is primarily associated with ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity. Response to xenobiotic stimulus alters cell or organism activity, such as movement, secretion, enzyme production, or gene expression. Exposure to xenobiotics triggers an inflammatory response, contributing to endothelial activation and dysfunction in MVA (Auerbach et al., 2022). The integral component of plasma membrane consists of gene products and protein complexes that maintain ionic gradients associated with elevated Na+/H+ exchange in MVA (Ronquist and Waldenström, 2003).

KEGG analysis indicates that MVA-associated signaling pathways mainly include pathways in cancer, lipid and atherosclerosis, human cytomegalovirus infection, and PI3K-Akt signaling pathway.

Cancer pathways involve PI3K/AKT/mTOR and Ras/MAPK (Yip and Papa, 2021). Inhibiting these pathways reduces inflammation and apoptosis, resulting in cardiovascular protection (Wang et al., 2017). The TNF signaling pathway is involved in the systemic inflammatory response and interacts with MAPK and NF-kappa B pathways, leading to disease progression (Li H. et al., 2022). Gancao, Jiegeng, Huangqi, and Xiebai block these pathways, acting as anti-inflammatory, antioxidant, anti-inflammatory, and anti-platelet aggregation agents and reducing endothelial dysfunction, foam cell formation, and vascular smooth muscle cell proliferation (Yao et al., 2016; Ding et al., 2022; Wu et al., 2023).

Atherosclerosis is a chronic inflammatory disease caused by lipid-rich plaques in arterial blood vessels. The lipid and atherosclerosis pathway is involved in inflammation, foam cell formation, LOX-1-mediated oxLDL uptake, apoptosis, plaque instability, and interacts with other pathways, leading to the progression of MVA (Pirillo et al., 2013).

Human cytomegalovirus (HCMV) is a double-stranded DNA virus that activates PDGFRA and PI3-K/AKT pathways, influencing the host immune system (Yu et al., 2023). It can induce endothelial injury, promote smooth muscle cell mutations, and increase polymorphonuclear leukocyte adhesion, leading to plaque formation and atherosclerosis (Nieto et al., 1996). HCMV infection may also increase the risk of restenosis after conventional coronary balloon angioplasty by inhibiting P53 function (Manegold et al., 1999).

The PI3K-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates essential cellular functions such as transcription, translation, proliferation, growth, and survival (Dunn and Connor, 2012). The PI3K/Akt/eNOS pathway regulates the phosphorylation of eNOS and modulates downstream pathways to regulate apoptosis and relax coronary microvessels (Chen R. et al., 2020).

NFKB1, ALB, AKT1, ACTB, TNF, IL6, ESR1, CASP3, and PTGS are the core targets in the PPI network. These genes may be very important in preventing and treating MVA. NF-kappa B, a transcription factor, regulates genes involved in immunity, inflammation, and cell survival (Romzova et al., 2006). It is associated with an inflammatory response, atherosclerosis, and endothelial dysfunction, affecting disease progression in MVA (Fiordelisi et al., 2019). The ALB gene encodes albumin, which possesses anti-inflammatory, antioxidant, anticoagulant, and antiplatelet aggregation activities, so hypoalbuminemia is an independent prognosticator of many cardiovascular diseases, including ischemic heart disease (Chien et al., 2017). AKT1 is relevant to the development of MVA due to its role in energy homeostasis, obesity, and brown fat organogenesis (Sanchez-Gurmaches et al., 2019). ACTB encodes β-actin, which is involved in vascular remodeling and contributes to cardiovascular disease (Yang et al., 2020). TNF induces intracellular signal pathways, inflammation, and immunity. IL-6 levels may be considered a diagnostic marker for MVA (Gurzău et al., 2021). Estrogen receptor alpha (ESR1) inhibits NF-κB signaling, decreasing inflammation-associated cytokines and activating nitric oxide synthase (NOS3) and endothelial NO production (Wu et al., 2022). Antidepressants have been proposed for treatment, with CASP3 gene expression positively correlated with depression duration and the number of episodes (Bliźniewska-Kowalska et al., 2023).

Nevertheless, our current study has certain limitations. The definition of MVA is vague, and there are no clear evidence-based diagnostic guidelines. Therefore, the homogeneity of MVA diagnoses in different literature retrieved cannot be guaranteed. In addition, the molecular docking technique still has some limitations, and the efficacy and safety of this MFHF should be rigorously verified by randomized controlled trials or systematic evaluations in the future.

MVA remains challenging, and understanding how to prevent this disease through diet is crucial. However, No previous studies have been conducted on the MFH for MVA. Our study introduces a novel multi-ingredient, multi-target, and multi-pathway MFHF to treat MVA, comprising PR, ASR, AMB, CR, AR, PR, and GRR. Leveraging network pharmacology and molecular docking, we identified key MFHF components targeting TCM patterns for MVA. These components, widely used in health foods and supplements with minimal toxicity, target core proteins (NFKB1, ALB, AKT1, ACTB, TNF, IL6, ESR1, CASP3, and PTGS) to modulate cancer, lipid and atherosclerosis, human cytomegalovirus infection, and the PI3K-Akt signaling pathway. Our findings suggest MFHF’s pleiotropic effects on MVA, including antioxidative, anti-inflammatory, analgesic, antiplatelet, vasodilatory, endothelial protective, and cardioprotective actions. This study provides insights into CMVD management, bridging ancient wisdom with modern science for healthcare, disease prevention, and natural therapies, thereby offering potential edible medication applications.