Traditional Chinese Medicine Treatment for Coronary Heart Disease: Pathological Mechanisms of Modulating Cell Death Pathways

Introduction

Cell death constitutes a fundamental physiological process across all living organisms, serving diverse roles that encompass embryonic development, organ homeostasis, aging, immune function, and the modulation of autoimmunity. The Cell Death Nomenclature Committee has established a classification system for cell death that distinguishes between two primary categories: accidental cell death and regulated cell death (RCD). The basis for this classification is a multifaceted framework encompassing morphological, biochemical, and functional criteria.¹ Accidental cell death is characterized as an uncontrolled biological event precipitated by unforeseen injurious stimuli.² Conversely, RCD is mediated by orchestrated signaling pathways that are integral to organismal development and tissue regeneration.³ Cardiovascular disease remains the foremost cause of mortality globally and represents a significant source of morbidity.⁴ Coronary heart disease (CHD) is characterised by functional impairments and structural lesions arising from coronary artery stenosis and inadequate myocardial perfusion, which culminate in clinical manifestations such as angina pectoris, sudden cardiac death, and myocardial infarction.⁵ The underlying pathology of CHD involves vascular and myocardial dysfunction driven by ischemia, hypoxia, oxidative stress, inflammation, and cell death processes.^6,7 The prevalence and mortality associated with CHD are escalating in both developed and developing nations.⁸ Established risk factors include hyperlipidemia, hyperglycemia, insulin resistance, and hypertension. As a chronic inflammatory disease, the pathogenesis of CHD implicates multiple cellular mechanisms, including necroptosis, apoptosis, ferroptosis, pyroptosis, and autophagy.⁹ Inflammation, the primary response of innate immunity, is considered essential in initiating and driving vascular diseases.¹⁰ Regulated cell death pathways are drivers, amplifiers, or regulators of inflammation in CHD. Nevertheless, the precise molecular mechanisms remain incompletely elucidated, and current therapeutic strategies are subject to ongoing debate. Consequently, there is a pressing need to identify novel therapeutic targets for CHD.

Traditional Chinese medicine (TCM) and its formulations are extensively employed in clinical settings, including for cardiovascular conditions. TCM typically functions as complex mixtures of herbs, where the therapeutic benefits arise from synergistic interactions among multiple bioactive components rather than isolated compounds. Existing research has largely focused on the effects of individual components on specific pathways, potentially failing to fully capture the holistic efficacy of traditional Chinese medicine formulations. Compared to single-target chemical drugs (such as statins for lipid-lowering), traditional Chinese medicine’s multi-target, multi-pathway approach aligns with the complex pathogenesis of CHD, involving oxidative stress and inflammation. TCM’s holistic regulation of diverse pathways holds unique therapeutic potential, yet challenges remain in elucidating mechanisms and achieving standardization. To address this research gap, this review further examines the impact of novel cell death (PANoptosis- Cuproptosis- Disulfidptosis) on the pathogenesis of CHD, offering new therapeutic directions. It also systematically reviews Chinese herbal extracts, compound formulations, and single herbs used to treat CHD. By integrating basic and clinical research findings, this study aims to elucidate the potential role of traditional Chinese medicine in CHD management.

Mechanisms of Different Cell Death Pathways in CHD

Cell death can be classified into programmed and unprogrammed types. Programmed cell death encompasses apoptosis, pyroptosis, autophagy, ferroptosis, and other forms.

Apoptosis-Context-Dependent Modulators

Apoptosis is a form of programmed cell death precisely regulated at the genetic level, facilitating the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or developmental processes.¹¹ While apoptosis eliminates impaired cells, excessive apoptosis can be detrimental. This process involves numerous cell-killing and phagocytic proteins and constitutes a caspase-dependent active death mechanism. It primarily engages pathway markers including Bcl-2, BAK, and Bax, which participate in multiple stages of CHD development such as atherosclerosis, myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure. Apoptosis in endothelial and smooth muscle cells weakens plaque structure and promotes rupture.¹² Oxidative stress and cholesterol overload are primary triggers. Statins (simvastatin) inhibit cardiomyocyte apoptosis by reducing Bax and caspase-3 expression while increasing Bcl-2 levels, thereby improving cardiac function post-myocardial infarction.¹³ The Fas/FasL pathway induces apoptosis by activating caspase-8, correlating with the severity of myocardial injury in CHD patients.¹⁴ Patients with end-stage heart failure exhibit substantially increased myocardial apoptosis rates linked to an imbalance between Bcl-2 and Bax.¹⁵ The process of apoptosis results in the loss of cardiomyocytes, thereby accelerating ventricular remodelling.¹⁶ Research indicates that myocardial ischemia/reperfusion injury is associated with apoptotic cell death. This process disrupts mitochondrial membrane integrity and promotes the cytoplasmic release of pro-apoptotic factors by activating pro-apoptotic Bcl-2 modulators BAX and BAK, thereby triggering caspase-dependent cell death.¹⁷ Liu proposed that long non-coding RNAs inhibit apoptosis and promote proliferation in human coronary artery endothelial cells by enhancing MAPK1 expression, demonstrating significant therapeutic potential for CHD.¹⁸

Autophagy-Context-Dependent Modulators

Autophagy is a conserved self-digestion process in eukaryotic cells that maintains cellular homeostasis through proteolysis.¹⁹ During autophagy, LC3 is cleaved into LC3I and LC3II. The conjugation of LC3I to phosphatidylethanolamine converts it into LC3II. LC3II associates with both sides of the autophagosome membrane, promoting autophagosome elongation and closure, ultimately engulfing mitochondria to form mitophagosomes. These mitophagosomes are then transported along microtubule tracks to lysosomes for degradation.²⁰ Through this process, cells degrade their own components within lysosomes. Autophagy exhibits a dual role: moderate activation clears damaged organelles, whereas excessive activation induces type II programmed cell death. Ischemic preconditioning mitigates myocardial injury by activating autophagy, while sustained ischemia triggers excessive autophagy, exacerbating cell death.²¹ It has been demonstrated by a number of studies that the process of macrophage autophagy exerts a significant influence on the development of atherosclerosis by promoting cholesterol efflux, suppressing inflammation, and inhibiting apoptosis.²² Defects in macrophage autophagy have been observed to accelerate foam cell formation, whereas enhanced autophagy has been shown to mitigate atherosclerosis.²³ Mitochondrial autophagy plays dual roles in myocardial ischemia-reperfusion injury: autophagy during ischemia is protective by clearing damaged mitochondria, but excessive activation during reperfusion may worsen cellular damage. Research shows that miR-499 reduces hypoxia/reoxygenation-induced myocardial cell injury by decreasing oxidative stress through Drp1-mediated mitochondrial autophagy.²⁴ The role of autophagy in CHD exhibits phase- and pathway-dependent. For example, autophagy during ischemia relies on AMPK activation to exert protective effects, whereas during reperfusion, it may exacerbate injury via Beclin 1-dependent mechanisms.^25,26 Fibroblast growth factor 21 (FGF21) has been demonstrated to play a pivotal role in a number of pathological processes, including vascular calcification, atherosclerosis and protection against myocardial ischemia-reperfusion injury. This function is thought to be achieved by inducing autophagy, thus suggesting a potential for FGF21 to be utilised as a therapeutic target.²⁷ Berberine alleviates myocardial injury in ischemic heart disease by modulating autophagy through mTOR and AMPK pathways.²⁸ Molecules such as circACR can reduce infarct size by inhibiting autophagy. Although mTORC1 inhibitors (rapamycin) can modulate autophagy levels, their clinical application requires caution.²⁹

Pyroptosis-Established Inflammatory Drivers in CHD

Pyroptosis is a highly inflammatory form of cell death characterised by membrane permeabilisation, the release of cellular contents (including proinflammatory cytokines) and cell lysis. It primarily involves the release of markers such as Gasdermin D, Caspase-1, Caspase-4, IL-1β, and IL-18.³⁰ Pyroptosis depends on inflammasome activation, with the released IL-1β/IL-18 exacerbating inflammation. The NLRP3 inflammasome activates the enzyme caspase-1, which in turn cleaves the substrate Gasdermin D, forming membrane pores. These pores result in the pyroptosis of endothelial cells and subsequent inflammation of the plaque, thus contributing to the development of atherosclerosis.^31,32 The process of pyroptosis in endothelial cells has been demonstrated to result in the disruption of endothelial barrier function, thereby promoting lipid deposition and monocyte infiltration.³³ In the context of macrophages, the release of inflammatory factors has been shown to contribute to plaque instability and to increase the risk of myocardial infarction.³¹ Finally, in smooth muscle cells, pyroptosis has been observed to accelerate fibrous cap degradation and to facilitate plaque rupture.³⁴ Pyroptosis is involved in the pathological processes of angina pectoris, myocardial infarction, ischemia-reperfusion injury, and heart failure. During myocardial ischemia, pyroptosis exacerbates cardiomyocyte death and inflammatory cascades, leading to ventricular remodeling.³³ Studies have demonstrated that monoclonal antibodies targeting Gasdermin D effectively suppress pyroptosis in atherosclerosis models.³⁵ Monoclonal antibodies targeting NLRP3 (MCC950), Caspase-1 (VX-765), or IL-1β (Canakinumab) have shown anti-atherosclerotic effects in clinical trials.³¹ Additionally, IL-1β antagonists (Anakinra) and IL-18 binding proteins have entered clinical trials, with preliminary results indicating reduced inflammatory markers in patients with CHD.³¹ Research indicates that certain TCM (Simiao Yong’an Decoction) reduce pyroptosis by inhibiting the NF-κB/NLRP3 pathway. The TCM theory of simultaneous treatment of heart and liver proposes regulating pyroptosis-related stasis toxins to delay the progression of atherosclerosis, thereby slowing the course of CHD.³⁶

Necroptosis-Established Inflammatory Drivers in CHD

Necroptosis is a regulated form of cell death that can be activated under conditions of apoptotic insufficiency.³⁷ It is mediated by the RIP1-RIP3-MLKL signaling cascade³⁸ and is closely associated with inflammation and oxidative stress. In the process of atherosclerotic plaque formation, oxidized low-density lipoprotein has been shown to promote plaque instability by inducing necroptosis in macrophages. This, in turn, accelerates the expansion of the necrotic core and the thinning of the fibrous cap.³⁹ Experimental studies have demonstrated that necrostatin-1, an oral inhibitor of necroptosis, reduces plaque area by 62% and increases smooth muscle cell content, thereby enhancing plaque stability and further lowering the incidence of CHD.⁴⁰ Following reperfusion after partial or complete acute occlusion of a sclerotic coronary artery, ischemic myocardium may experience progressive and irreversible tissue damage despite restored blood supply,⁴¹ increasing susceptibility to myocardial infarction. RIP3 activates the CaMKII-mPTP pathway, leading to mitochondrial dysfunction and cardiomyocyte death. These findings establish CaMKII as a novel RIP3 substrate and delineate the RIP3-CaMKII-mPTP pathway for cardiomyocyte programmed necrosis, representing a promising therapeutic target for treating ischemia- and oxidative stress-induced myocardial injury and heart failure.⁴² In animal models, inhibiting RIP1 or knocking out RIP3 reduces infarct size and improves left ventricular function.⁴³ Concurrently, inhibitors targeting RIP1/RIP3 (NEC-1) and MLKL antagonists demonstrate potential for reducing myocardial injury in experimental settings.⁴⁴ Further studies indicate that liraglutide may mitigate myocardial ischemia/reperfusion injury partly by inhibiting programmed necrosis and partly by enhancing activity in the GLP-1R/PI3K/Akt pathway.⁴⁵

Ferroptosis-Established Inflammatory Drivers in CHD

Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation,⁴⁶ which is associated with abnormalities in iron metabolism and ultimately leads to cell membrane disruption and cell death. The mechanisms underlying ferroptosis primarily involve dysregulation of iron metabolism, lipid peroxidation, glutathione depletion, and reduced GPX4 activity.⁴⁷ Iron overload induces mitochondrial lipid peroxidation, triggering endothelial dysfunction, promoting plaque formation, and exacerbating ischemia-reperfusion injury. Concurrently, iron overload may enhance platelet aggregation and thrombosis, increasing the risk of acute coronary events.^48,49 Fang found that ferritin H deficiency exacerbates myocardial ferroptosis via SLC7A11-mediated glutathione depletion, whereas SLC7A11 overexpression improves cardiac function by elevating glutathione levels.⁵⁰ Ferroptosis regulates macrophage polarization toward a proinflammatory phenotype, increasing plaque inflammation and oxidative stress, which leads to plaque instability.⁵¹ Thus, targeting ferroptosis reduces macrophage lipid accumulation and necrotic core formation.⁵² In animal models, ferroptosis inhibitors (Ferrostatin-1, Liproxstatin-1) reduce cardiomyocyte death by inhibiting lipid peroxidation, thereby decreasing myocardial injury.^50,53 Iron chelators (deferasirox) and low-iron diets reduce cardiac iron deposition and improve the prognosis of CHD.⁵⁴ Research found that TCM components such as paeoniflorin and tanshinone inhibit ferroptosis by regulating Nrf2/HO-1 signaling activation, demonstrating anti-atherosclerotic and cardioprotective effects in animal models.⁵⁵ Multiple epidemiological studies have established a positive correlation between elevated iron levels and the incidence and mortality of CHD. For example, a meta-analysis demonstrated that increased serum ferritin levels are significantly associated with a higher risk of cardiovascular events in the general population.⁵⁶

PANoptosis-Emerging/Hypothetical Mechanisms

The concept of PANoptosis was first proposed by Dr. Kanneganti in 2019.⁵⁷ PANoptosis is defined as an inflammatory form of cell death regulated by the PANoptosis pathway, exhibiting key features of pyroptosis, apoptosis, and necroptosis.⁵⁸ Studies have shown that during myocardial ischemia/reperfusion injury, the expression levels of multiple molecules-including caspase-8, caspase-3, NLRP3, caspase-1, Gasdermin D, RIPK1, RIPK3, and MLKL-significantly increase over time in injured cardiac tissue, indicating that PANoptosis occurs in ischemic/reperfused hearts.⁵⁹ Additionally, ACP5 and HO-1 have been identified as potential atherosclerosis-associated genes linked to PANoptosis. These genes may contribute to atherosclerosis pathogenesis by regulating macrophage PANoptosis.⁶⁰ Further studies demonstrate that inhibiting ZBP1 expression significantly reduces the levels of PANoptosis regulatory proteins, thereby exerting a cardioprotective effect against myocardial ischemia/reperfusion injury.⁶¹ Although bioinformatics analyses have revealed substantial associations between multiple PANoptosis-related genes and cardiovascular diseases, experimental validation remains lacking. Therefore, further experimental studies are necessary to confirm the role of PANoptosis in cardiovascular diseases.

Cuproptosis-Emerging/Hypothetical Mechanisms

Copper acts as a catalytic cofactor in various physiological processes, including energy metabolism, mitochondrial respiration, and antioxidant defense. Generally, intracellular copper levels remain relatively low. However, when copper accumulates within cells, excess copper binds to mitochondrial proteins, triggering protein toxicity stress-mediated cell death-a phenomenon termed cuproptosis.⁶² Ferrodoxin is a key regulator of cuproptosis and an upstream modulator of protein lipoylation. Yang used bioinformatics analysis and in vitro experiments to suggest that Ube2d3 further influences the progression of myocardial infarction by regulating cuproptosis.⁶³ Research indicates that cuproptosis-related genes may contribute to the onset and development of acute myocardial infarction via the HIF-1 signaling pathway. Nevertheless, the mechanisms underlying their involvement require further validation in human, animal, and cellular models to provide novel insights for the diagnosis, prognosis, and treatment of acute myocardial infarction.⁶⁴ In their study, Zhang utilised advanced analytical techniques, including differential and correlation analyses, to investigate the immune microenvironment in both healthy controls and patients suffering from CHD.⁶⁵ This analysis led to the identification of several cuproptosis-related genes that have the potential to serve as diagnostic biomarkers and therapeutic targets for CHD. These findings provide novel insights that could shape future scientific research in this field.

Disulfidptosis-Emerging/Hypothetical Mechanisms

In 2023, Professor Gan Boyi’s research group discovered a novel mechanism of cell death induced by disulfide stress, which they named disulfidptosis. Unlike other cell death pathways, studies show that disulfidptosis cannot be inhibited by drugs commonly used to suppress cell death, nor can it be prevented by knocking out key genes involved in ferroptosis/apoptosis. However, thiol oxidants such as diamides and diethyl maleate significantly enhance this cell death pathway, hence the designation “disulfidptosis”.⁶⁶ The mechanism involves elevated cysteine levels and subsequent depletion of nicotinamide adenine dinucleotide phosphate (NADPH), triggering massive intracellular accumulation of disulfide bonds.⁶⁷ SLC7A11 is a transporter responsible for moving cysteine from the extracellular to the intracellular space. Under glucose deprivation, increased SLC7A11 expression leads to substantial cysteine accumulation, which subsequently induces disulfide stress and causes cell death.^66,68 Thus, the activation of disulfidptosis likely requires three key factors: (1) high expression of SLC7A11, which imports extracellular cysteine and exports intracellular glutamate, resulting in elevated cysteine uptake and excessive intracellular cysteine accumulation, thereby causing disulfide stress in cellular metabolism;^68,69 (2) impaired glucose metabolism under glucose-deprived conditions, which prevents the generation of reduced NADPH via the pentose phosphate pathway;⁷⁰ and (3) abnormal disulfide bond formation between actin cytoskeletal proteins. Currently, research on disulfidptosis has primarily focused on cancer and neurodegenerative diseases. Fan revealed a potential association between disulfidptosis and hypertrophic cardiomyopathy, proposing a predictive model for disulfidptosis-related genes, including GYS1, MYH10, SLC3A2, and CAPZB. This model enabled the identification of novel therapeutic drugs targeting core genes through gene prediction.⁷¹ Through bioinformatics analysis, Zhao identified four disulfide-related genes dysregulated in heart failure samples, highlighting the critical role of these genes in shaping the diversity and complexity of the heart failure immune microenvironment.⁷² Bioinformatics analysis and in vitro experiments demonstrated altered expression of key disulfide-related genes MYH9, NUBPL, MYL6, MYH10, and NCKAP1 in ischemic myocardial regions, elucidating the significance of disulfide-related cell death in ischemic cardiomyopathy and underscoring the diagnostic potential of the identified core genes.⁷³ Findings by Wang suggest that disulfidptosis may promote the progression of type A aortic dissection by inducing immune responses and metabolic activities. This research provides new insights into the pathogenesis and identifies potential therapeutic targets for type A aortic dissection.⁷⁴ We summarize the mechanisms of different cell death pathways in CHD in Figure 1.

Figure 1 The Mechanisms of Different Cell Death Pathways in CHD.

TCM Treats CHD by Regulating Cell Death

TCM Modulates Apoptosis to Intervene in CHD

Tanshinone IIA is a liposoluble diterpene extracted from Salvia miltiorrhiza that alleviates myocardial ischemic injury. It enhances the viability of damaged cardiomyocytes and inhibits apoptosis by increasing the expression of Bcl-2 and Bak in myocardial tissue while decreasing the expression of Cyt-c, caspase-3, and Apaf-1.⁷⁵ Tanshinonic acids A and B, active components of Salvia miltiorrhiza, exhibit significant pharmacological activities. Treatment with tanshinonic acid A reduces tunnel-positive cells and pro-apoptotic Bax following myocardial infarction. Further studies indicate that it promotes thioredoxin and inhibits c-JNK activation, thereby mitigating inflammation and apoptosis post-myocardial infarction.⁷⁶ Tanshinol B alleviates myocardial ischemia/reperfusion injury by activating PI3K/Akt signaling and inhibiting HMGB1 expression, thereby improving cardiac function and reducing infarct size.⁷⁷ Research found that Acorus tatarinowii volatile oil inhibits myocardial infarction-induced apoptosis by downregulating COX-2 and upregulating PPAR protein, thereby alleviating myocardial ischemia.⁷⁸ Tongmai Yangxin Pills are commonly used to treat CHD, arrhythmia, and chest pain. Their potential mechanism may involve enhancing eNOS activity and eNOS Ser (1177) phosphorylation levels in the myocardium, increasing Bcl-2 expression, while simultaneously reducing caspase-3 and Bax expression, thereby inhibiting myocardial cell apoptosis.⁷⁹ In the systematic review of randomized clinical trials on Tongmai Yangxin Pills, a total of nine randomized controlled trials were included. Only one study reported adverse events, while five studies reported no adverse events.⁸⁰ The beneficial effects of Rhodiola rosea injection on myocardial ischemia/reperfusion injury involve improving mitochondrial function, regulating autophagy, and inhibiting apoptosis through the AMPK/mTOR pathway. It significantly reduces cleaved caspase-3 and increases the Bcl-2/Bax ratio,⁸¹ thereby further controlling the progression of CHD.

TCM Modulates Autophagy to Intervene in CHD

Huang’s research suggests that epiberberine protects cardiomyocytes during myocardial ischemia/reperfusion by inhibiting autophagy activation, positioning it as a promising therapeutic agent for treating ischemia/reperfusion-induced cardiomyocyte injury.⁸² Hesperidin reduces myocardial ischemia/reperfusion injury by inhibiting excessive autophagy, with activation of the PI3K/Akt/mTOR pathway contributing to hesperidin’s inhibitory effect on excessive autophagy.⁸³ Qin’s research demonstrated that ginsenoside Rb1 protects against myocardial ischemia/reperfusion injury by inhibiting cardiomyocyte autophagy through the PI3K/Akt/mTOR signaling pathway.⁸⁴ The Yiqi Huoxue Decoction is a prescription designed to tonify qi, strengthen the spleen, resolve stasis, and unblock collaterals. It primarily consists of herbs such as Astragalus, Fried Atractylodes, Poria, and Ligusticum. Research indicates that this formula may mitigate myocardial ischemia/reperfusion injury by targeting mitochondrial autophagy, potentially serving as a therapeutic strategy for this condition.⁸⁵ Su Xiao Jiu Xin Wan, a frequently administered Chinese patent medicine, contains primary components such as Chuanxiong and Borneol. It has been demonstrated to alleviate autophagy-related myocardial ischemia/reperfusion injury by downregulating miR-193a-3p, enhancing ALKBH5 expression, and reducing m6A methylation. This mechanism may be attributed to its constituents Ligustilide A and synthetic Dextrorotatory Borneol.⁸⁶

TCM Modulates Pyroptosis to Intervene in CHD

Cinnamic acid, an active phenolic compound extracted from cinnamon, exerts cardioprotective effects against myocardial ischemia/reperfusion injury by inhibiting NLRP3 inflammasome-mediated inflammation and cardiomyocyte pyroptosis.⁸⁷ Zhang et al demonstrated that resveratrol glycoside exerts anti-atherosclerotic effects by suppressing inflammation and pyroptosis through blocking the NLRP3/caspase-1 pathway and activating mTOR-mediated autophagy.⁸⁸ Chen showed that administration of Astragalus-Panax ginseng granules confers cardioprotective effects by inactivating the NF-κB/NLRP3/Gasdermin D pathway in myocardial infarction, resulting in improved cardiac function, reduced inflammatory cell infiltration and collagen deposition, and suppression of NLRP3 inflammasome activation and pyroptosis.⁸⁹ Emodin enhances in vitro cell survival and reduces in vivo myocardial infarction size by inhibiting ischemia/reperfusion-induced pyroptosis and decreasing the expression of pyroptosis-associated proteins.⁹⁰ Guizhi Tongluo Pian, an herbal formulation composed primarily of Radix Pseudostellariae, Cortex Phellodendri, Rhizoma Dioscoreae Oppositae, and Poria, has been shown to inhibit vascular inflammation and macrophage pyroptosis via the Piezo1/NLRP3 signalling pathway.⁹¹ This has been demonstrated to result in a delay in atherosclerosis progression, thus providing a potential therapeutic target for the treatment and development of drugs for atherosclerosis. Danshen Decoction prevents cardiac injury by inhibiting activation of the TXNIP/NLRP3/caspase-1 signaling pathway, thereby reducing cardiomyocyte pyroptosis and providing a theoretical basis for treating myocardial ischemia/reperfusion injury.⁹²

TCM Modulates Necroptosis to Intervene in CHD

It has been demonstrated through rigorous research that Tanshinone I has the capacity to alleviate programmed cell necrosis by inhibiting the RIP1/RIP3/MLKL pathway and activating the Akt/Nrf2 signalling pathway. This process has been shown to exert cardiovascular protective effects both in vitro and in vivo. It holds potential for development as a cardiovascular protective agent.⁹³ Xing showed that quercetin inhibits necrosis in ischemic/reperfused cardiomyocytes by coordinating mitochondrial quality control through the DNA-PKcs-SIRT5 axis, providing additional protection to cardiomyocytes.⁹⁴ Sugarcane leaf polysaccharides mitigate oxidative stress and necrotic apoptosis by regulating the Nrf2/HO-1 and RIP1/RIP3/MLKL signaling pathways, playing a crucial role in cardiovascular protection and holding promise for development as novel drugs for cardiovascular diseases.⁹⁵ TCM formulas possess multi-component and multi-target characteristics. Compound Danshen Droplet Pills, composed of Danshen (Salvia miltiorrhiza), Sanqi (Panax notoginseng), and Bingpian (Borneol), regulate qi and relieve pain, promote blood circulation, and remove blood stasis. They are indicated for treating blood stasis patterns. These pills inhibit RIPK3-related pathways while simultaneously modulating the AKT/GSK-3β/β-catenin pathway, suppressing epithelial-mesenchymal transition in cardiomyocytes, and reducing fibrosis and left ventricular remodeling.⁹⁶ According to the pooled results of clinical drug trials, the combination of Western medicine with compound Danshen Droplet Pills demonstrates favorable safety in the treatment of stable angina pectoris. It is characterized by minimal adverse reactions (primarily gastrointestinal) and high patient tolerability.⁹⁷ The Liqi Huoxue Droplet Pill formulation includes Miao medicinal ingredients such as Litsea lancilimba Merr. oil, Allium macrostemon Bunge, Sichuan lovage rhizome, and Borneolum Syntheticum.⁹⁸ Its mechanism involves protecting myocardial cells from ischemia-reperfusion injury by inhibiting necrotic apoptosis in rats.⁹⁹

TCM Modulates Ferroptosis to Intervene in CHD

Naringenin is a major flavonoid found in various citrus fruits, bergamot, and tomatoes. It suppresses inflammation, lipid peroxidation, and ferroptosis induced by myocardial ischemia-reperfusion injury by activating the Nrf2/GPX4 pathway.¹⁰⁰ Resveratrol, the primary compound extracted from Polygonum cuspidatum, has been shown by Li to prevent myocardial ischemia/reperfusion injury by inhibiting oxidative stress and ferroptosis.¹⁰¹ Gegen Qinlian Decoction is a classical prescription used to treat unexplained superficial syndrome caused by exogenous pathogenic factors. It contains chemical constituents such as flavonoids, alkaloids, saponins, phenolic acids, coumarins, and lignans.¹⁰² Research discovered that this decoction modulates the expression of iron-related genes, reduces lipid peroxidation levels in myocardial tissue, and upregulates GPX4 protein expression.¹⁰³ Shexiang Baoxin Wan possesses effects that promote blood circulation, relieve pain, restore yang, and expel pathogenic factors. Research indicates that Shexiang Baoxin Wan also inhibits myocardial remodeling, improves vascular endothelial function, promotes angiogenesis, reduces plaque formation, and mitigates myocardial ischemia/reperfusion injury.¹⁰⁴ Ye found that Shexiang Baoxin Wan reduces myocardial iron overload by modulating the miR-144-3p/SLC7A11 signaling pathway.¹⁰⁵ Clinical trials have revealed that adverse reactions (such as tongue numbness, gastrointestinal reactions, palpitations, and rashes) occurred less frequently in the intervention group than in the control group.¹⁰⁶ Other clinical studies have also demonstrated adverse reactions associated with Shexiang Baoxin Wan, including decreased blood pressure and heart rate, as well as abnormal liver and kidney function during treatment.¹⁰⁷ Most clinical trials on Shexiang Baoxin Wan have not identified significant adverse reactions.¹⁰⁸ Shengmai San has qi-tonifying, pulse-activating, yin-nourishing, and fluid-promoting effects and is commonly used clinically to treat qi-yin deficiency, palpitations, dyspnea, and spontaneous sweating with a weak pulse. Mei found that Shengmai San activates Nrf2/GPX4-mediated ferroptosis to mitigate myocardial ischemia/reperfusion injury.¹⁰⁹ The Shengmai preparation combined with Western medicine combination favorably impacts cardiovascular events, angina symptoms, endothelial function, platelet aggregation, and blood viscosity, with comparable safety to that of routine Western medicine.¹¹⁰

TCM Modulates PANoptosis to Intervene in CHD

PANoptosis is a recently identified form of cell death, first described in 2019, that integrates key features of pyroptosis, apoptosis, and necroptosis. Xianlinggubao Capsules, a well-known traditional Chinese herbal formula, are acclaimed for their ability to nourish yin and replenish blood, promote blood circulation and remove blood stasis, regulate the immune system, and enhance bone density.¹¹¹ Research has shown that Xianlinggubao Capsules can reverse myocardial injury following myocardial infarction by inhibiting the NLRP3/Caspase-3/RIP1-mediated PANoptotic pathways.¹¹² Xiao Chai Hu Decoction, a classic TCM formula, contains ingredients such as Bupleurum, Scutellaria, Pinellia, Ginseng, and Ginger. Wang proposed that Xiao Chai Hu Decoction protects against sepsis-induced cardiomyopathy by inhibiting ZBP1-triggered PANoptosis.¹¹³ It is evident that the research conducted on PANoptosis has been predominantly focused on the domains of cancer and neurodegenerative diseases, with a paucity of investigation directed towards cardiovascular disorders. Consequently, the effects of TCM on CHD remain largely theoretical.

TCM Modulates Cuproptosis to Intervene in CHD

TCM primarily focuses on heat-clearing and toxin-eliminating therapies for cuproptosis, supplemented by diuretic treatments. In contrast, western medicine typically employs copper-chelating agents, such as ammonium tetrathiomolybdate-a small hydrophilic compound capable of highly specific copper chelation.¹¹⁴ Triethylenetetramine, a chelating agent that specifically and selectively binds copper ions, has been used as a second-line treatment for Wilson’s disease.¹¹⁵ Copper carrier 8-hydroxyquinoline and its derivatives possess metal-chelating capabilities and exhibit broad biological applications across various disease states, ranging from neurodegenerative disorders to cancer.¹¹⁶ Curcumin compounds are the primary bioactive constituents identified in the traditional Chinese herbal formula Gancao Decoction, and these components have been detected in rat liver tissue. Research has demonstrated that turmeric may also be utilized for the treatment of cuproptosis.¹¹⁷ Curcumin belongs to the flavonoid class of compounds. The mechanism of action of flavonoids in treating cuproptosis may be related to their hydroxyl and double-bond structures, which enable them to form complexes with metal ions and regulate metal concentrations. Consequently, certain TCM formulations may exhibit therapeutic effects against cardiovascular diseases and cuproptosis.^118,119

TCM Modulates Disulfidptosis to Intervene in CHD

Disulfidptosis is a newly identified form of cell death characterized by cytoskeletal disintegration triggered by the abnormal accumulation of intracellular disulfide bonds. This process is induced by disulfide stress resulting from glucose deprivation and was first described by cancer researchers.¹²⁰ TCM researchers propose that the herbal compound dragon’s blood provides multi-target neurovascular protection in ischemic stroke by modulating inflammation, preserving blood-brain barrier integrity, and inhibiting disulfidptosis, highlighting its potential as a therapeutic candidate.¹²¹ Additionally, bioinformatics analyses have identified sulfide-related genes, which were validated in mouse models using Western blotting, RNA sequencing, and immunohistochemistry. This led to the selection of resveratrol as a core target compound for developing therapeutics against hypertrophic cardiomyopathy.⁷¹ However, most studies on cardiovascular diseases associated with disulfidptosis remain limited to bioinformatics analyses, with minimal multi-level in vitro validation. Research on specific cardiovascular conditions, such as CHD, is even more scarce. Therefore, the precise mechanisms of disulfidptosis in CHD and the therapeutic efficacy of TCM treatments require further systematic experimental validation. We summarize the mechanisms of action of common Chinese herbs and formulas in Table 1.

Table 1 Mechanisms of Action of TCM Compound Preparations in Regulating Cell Death to Intervene in CHD

Of note, one should bear in mind that TCM medications are usually prescribed as complex formulae, which are often further manipulated by the practitioner on a personalized basis. Moreover, most active ingredients isolated from TCM may target multiple molecules or pathways. Most basic experiments face obstacles in translating to human clinical practice. According to adverse reaction reports from multiple drug clinical trials, adverse reactions associated with TCM are predominantly linked to sudden cardiogenic death, heart failure, angina pectoris, gastrointestinal systemic adverse reactions, and skin rash. Meanwhile, the limitations of traditional Chinese medicine lie in: 1) Its diverse composition, making quantitative characterization challenging; 2) The absence of rigorous approval procedures for TCM products on the Chinese market, unlike Western pharmaceuticals, rendering their efficacy and safety unverifiable; 3) Small sample sizes in randomized controlled trials, reliance on surrogate endpoints, short patient follow-up periods, and inconsistent outcomes. Meanwhile, since emerging/hypothetical mechanisms cell death remain understudied, PANoptosis research primarily focuses on cancer, cuproptosis studies are predominantly animal-based, and disulfidptosis remains largely theoretical. Not surprisingly, we are facing immense challenges in interpreting the observed therapeutic benefits of TCMs with contemporary pharmacological approaches by pinpointing individual compounds and their molecular targets.

Conclusions

Cell death plays a crucial role in the onset and progression of CHD. The pathological mechanisms of CHD are closely linked to multiple cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, PANoptosis, cuproptosis, and disulfidptosis. These pathways serve as important therapeutic targets by regulating processes such as atherosclerotic plaque stability, myocardial ischemia/reperfusion injury, and ventricular remodeling. Inflammasomes can induce cell death, and cell death can activate inflammasomes. Therefore, inflammation also plays a relatively central role in linking these cell death pathways to the progression of CHD. In recent years, targeted treatments for CHD using TCM and herbal formulas have yielded promising results. Despite significant achievements in treating CHD, TCM faces numerous practical limitations. For instance, clinical research often suffers from inconsistent trial designs, unreasonable efficacy assessment criteria, lack of unified diagnostic standards, insufficient sample sizes, absence of dynamic follow-up, and scarcity of multicenter, double-blind randomized controlled trials. In basic research, limitations exist in validating the success of animal model development, potentially resulting in models that fail to accurately reflect the clinical efficacy and mechanisms of TCM treatment. Most natural products discussed in this review have been evaluated only in preliminary pharmacological studies, and the molecular mechanisms underlying their anti-CHD activity remain poorly understood. Research on the mechanisms of action of TCM formulas often carries speculative elements, with many analyses relying on bioactive compounds identified in their key constituents. The reductionist approach of studying isolated compounds, while mechanistically informative, may overlook the synergies inherent in TCM formulations. Future research should integrate quantitative systems pharmacology to decode the multi-target, multi-component characteristics of TCM. Meanwhile, we are developing multi-target inhibitors by identifying cross-regulatory nodes among cell death pathways such as PANoptosis, ferroptosis, cuproptosis, and disulfidptosis. Disulfidptosis, as a newly discovered form of cell death, also represents a promising new direction for research.