Panax ginseng Across the Cardiovascular Continuum: Molecular Targets, Mechanistic Convergence, and Translational Challenges

Abstract

Cardiovascular diseases develop through an interconnected continuum that extends from cardiometabolic risk factors and vascular dysfunction to myocardial ischemic injury, pathological remodeling, and heart failure. Panax ginseng and its bioactive constituents have shown cardiovascular protective effects in various experimental models. However, the molecular mechanisms shared across different stages of the cardiovascular continuum remain insufficiently integrated. This review critically synthesizes current evidence on Panax ginseng, ginseng-derived constituents, and ginseng-containing preparations across major stages of cardiovascular disease. Particular emphasis is placed on convergent molecular networks involving metabolic and mitochondrial homeostasis, oxidative stress and inflammation, autophagy and mitophagy, regulated cell death, calcium handling, vascular and fibrotic remodeling, and gut microbiota–host interactions. Several target-oriented mechanisms, including peroxisome proliferator activated receptor (PPAR) γ, ryanodine receptor 2, histone acetyltransferase P300/dihydrolipoamide dehydrogenase/pyruvate dehydrogenase, Fas-associated death domain/PPARα, and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2A-associated regulation, are highlighted and distinguished from pathway-level or phenotypic evidence. Despite extensive preclinical data, direct target engagement, causal validation, pharmacokinetic characterization, preparation standardization, and clinical evidence remain limited. Integrating target-level validation with standardized ginseng interventions and clinically relevant models may provide a stronger molecular basis for evaluating the cardiovascular potential of ginseng.

1. Introduction

With the global aging population and the growing prevalence of unhealthy lifestyles, the incidence of cardiovascular diseases (CVDs) is constantly rising and has become a major cause of death and disability [1]. CVDs are defined as a series of events called the cardiovascular continuum first proposed by Victor J. Dzau. This concept describes a sequence of interrelated events that begins with risk factors, such as obesity, dyslipidemia and diabetes, which collectively constitute metabolic syndrome, then it gradually progresses to atherosclerosis, coronary artery disease, myocardial ischemia, coronary thrombosis, myocardial infarction, arrhythmia, remodeling, ventricular enlargement, heart failure, and ultimately leads to death [2]. Pharmacological interruption of the cardiovascular continuum effectively reduces cardiac-related mortality and is therefore of profound clinical importance.

Panax ginseng C. A. Mey (Ginseng, Renshen), a representative traditional Chinese medicine, has been used for centuries to improve lipid profiles, enhance cardiac function, and reduce hypertension for preventing and treating cardiovascular conditions [3]. Clinically, ginseng-containing formulas have been used as adjunctive therapies for heart failure [4] and coronary heart disease [5], while experimental evidence further supports their roles in alleviating myocardial hypertrophy [6], fibrosis [7], ischemia/reperfusion injury [8], and pathological cardiac remodeling [9]. Modern pharmacological research has confirmed that ginseng contains numerous active constituents that exert cardiovascular protective effects, including ginsenosides, polysaccharides, peptides, and other small molecules [10], which may act through multiple mechanisms such as anti-inflammatory, anti-oxidant, anti-apoptotic, anti-fibrotic, and metabolic regulatory effects [11,12]. Through multiple pathways and targets, ginseng and its bioactive constituents may modulate pathological processes at multiple stages of the cardiovascular continuum, ranging from cardiometabolic risk and vascular dysfunction to myocardial ischemic injury, pathological remodeling, and heart failure. Previous reviews have summarized the cardiovascular pharmacological effects and therapeutic applications of ginseng and ginsenosides [3], highlighted their protective mechanisms, particularly those involving energy metabolism and adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator activated receptor (PPAR) signaling [10] and evaluated preclinical and clinical evidence, including safety and toxicity considerations [11]. Other reviews have largely focused on individual cardiovascular conditions, such as cardiac ischemia/reperfusion injury [13] or heart failure [14]. However, the molecular mechanisms that converge across different stages of the cardiovascular continuum, as well as the strength of evidence supporting specific molecular targets, remain insufficiently integrated.

Using the cardiovascular continuum as a conceptual framework, this review critically synthesizes current evidence on the cardioprotective actions of ginseng, ginseng-derived constituents, and ginseng-containing preparations across major stages of cardiovascular disease. Rather than merely cataloguing disease-specific effects, we focus on shared mechanistic networks involving metabolic and mitochondrial homeostasis, oxidative stress and inflammation, regulated cell death, autophagy and mitophagy, vascular homeostasis, and pathological remodeling. This review could provide a basis for its rational clinical application and future research (Figure 1). The interventions discussed in this review encompass ginseng extracts, isolated ginsenosides, ginseng-derived polysaccharides, microbial metabolites of ginsenosides, synthetic ginsenoside derivatives, and multiherbal formulations containing ginseng, these interventions differ in composition, pharmacokinetic properties, and potential biological effects. Therefore, their findings are discussed according to the specific intervention investigated, and the effects observed with isolated compounds or multiherbal formulations are not automatically attributed to ginseng extracts.

Figure 1. Overview of the cardiovascular continuum and the major cardioprotective mechanisms of ginseng and its related interventions. The upper panel illustrates the progression of the cardiovascular continuum from cardiometabolic risk factors and atherosclerosis to myocardial ischemic injury, pathological cardiac remodeling, and heart failure. The middle panel summarizes the major mechanistic networks associated with the cardiovascular effects of ginseng, including antioxidative and immunomodulatory actions, regulation of mitochondrial function and autophagy, modulation of regulated cell death, promotion of angiogenesis, and gut microbiota regulation. The lower panel presents representative ginseng-derived constituents and selected ginseng-containing multi-herbal formulations discussed in this review. The arrow indicates the progression of the cardiovascular continuum. The colors are used solely for visual differentiation and do not convey any specific biological or clinical significance. This figure was created by the authors based on a synthesis of the existing literature.

2. Cardiometabolic Risk Factors

Cardiometabolic risk factors, including obesity, insulin resistance, dyslipidemia, hypertension, and hyperglycemia, represent the early stages of the cardiovascular continuum and collectively contribute to subsequent vascular and myocardial injury. These metabolic abnormalities are closely interconnected through the disturbances in energy homeostasis, chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and impaired glucose and lipid metabolism. Accumulating preclinical evidence suggests that Panax ginseng and its bioactive constituents may modulate several of these pathological processes, supporting their potential roles in the early cardiometabolic stages of cardiovascular disease.

2.1. Obesity and Insulin Resistance

Obesity and insulin resistance are closely interconnected cardiometabolic abnormalities that substantially increase cardiovascular risk. Obesity results from a chronic imbalance of energy homeostasis, in which calorie intake exceeds calorie expenditure. It is accompanied by adipose tissue dysfunction and dysregulated inflammatory adipocytokine secretion, which contribute to cardiovascular structural and functional alterations and broader metabolic abnormalities [15]. Insulin resistance is a central pathological feature of metabolic syndrome and contributes to impaired glucose utilization, compensatory hyperinsulinemia, and subsequent cardiometabolic dysfunction [16,17]. Increasing preclinical evidence suggests that ginseng and its bioactive constituents may modulate these abnormalities through coordinated effects on adipocyte function, energy metabolism, insulin signaling, and mitochondrial homeostasis. In addition to improving glucose and lipid metabolism, ginseng-derived constituents may alleviate insulin resistance through modulation of insulin signaling and mitochondrial quality control. For example, the malonyl-ginsenosides from Panax ginseng activate the insulin receptor substrate-1/phosphatidylinositol3-kinase (PI3K)/protein kinase B (AKT) and AMPK signal pathways to improve glucose and lipid metabolism and insulin resistance [18]. Compound K (CK) also attenuates skeletal-muscle insulin resistance by triggering dynamin-related protein 1 (Drp1)/PINK1-dependent mitophagic activity [19]. These findings suggest that restoration of insulin signaling and mitochondrial homeostasis may contribute to the metabolic effects of ginseng-derived constituents, although the direct molecular targets underlying these effects remain to be clarified.

2.1.1. Promotion of Adipocyte Browning

The browning of white adipose tissue, namely the conversion of white adipocytes into beige or brown-like adipocytes, is critical in counteracting obesity [20]. Rb1 facilitates the browning of white adipocytes, whereas Rb2 enhances brown adipose activity and induces white adipose tissue browning, accompanied by AMPK activation and increased expression of thermogenic and mitochondrial genes [21,22]. Ginsenoside F1 has also been reported to promote adipocyte browning [23]. Collectively, these findings suggest that the enhancement of thermogenic adipocyte activity may represent one mechanism by which ginseng-derived constituents improve obesity-related metabolic dysfunction. However, the available evidence remains predominantly preclinical, and whether these effects translate into clinically meaningful improvements in cardiometabolic risk remains unclear. A similar browning-promoting effect has also been reported for Shengmai San, a multi-herbal formula containing ginseng, although this effect cannot be attributed specifically to ginseng itself [24].

2.1.2. Regulation of the Gut Microbiota

The gut microbiota plays a key causal role in the development of diet-induced obesity [25]. Pretreatment with ginseng polysaccharides has been shown to regulate fecal microbiota and hepatic lysine degradation, thereby attenuating obesity and liver lipid accumulation [26]. A novel polysaccharide, a homogeneous ginseng polysaccharide, increases the expression of tight junction proteins and regulates the gut microbiota thereby reducing body weight and alleviating hepatic lipid accumulation and inflammatory injury [27]. In addition, (20R)-panaxadiol may ameliorate obesity, at least in part, by modulating the gut microbiota [28]. Ginsenosides have also been reported to improve high-fat diet (HFD)-induced hepatic lipid disorders via gut microbiota modulation and cholesterol signaling regulation [29]. These findings suggest that microbiota-mediated metabolic regulation may contribute to the anti-obesity effects of ginseng-derived constituents, although the specific microbial metabolites and host targets responsible for these effects remain incompletely defined.

2.1.3. Inhibition of Adipogenesis and Lipogenesis

Another important mechanism underlying the anti-obesity effects of ginseng is the inhibition of adipocyte differentiation and lipid accumulation. Adipogenesis, the process by which adipocyte precursor cells undergo proliferation and differentiation, is a fundamental mechanism underlying adipose tissue expansion [30]. Several ginsenosides have been reported to suppress these processes, with PPARγ and CCAAT/enhancer binding protein alpha (C/EBPα) emerging as recurrent regulatory nodes. Rf and F2 inhibit adipocyte differentiation through PPARγ-related mechanisms, whereas Rc, Rg3, the Rg5/Rk1 mixture, and Rh2 reduce adipogenesis by downregulating PPARγ and/or C/EBPα signaling [31,32,33,34,35,36]. Another study indicates that Rg3 inhibits signal transducer and activator of transcription 5 (STAT5) phosphorylation and suppresses PPARγ expression in HFD models, leading to downregulation of lipogenic proteins [37]. AMPK-dependent regulation also appears to contribute to these effects, as F2, Rg1, Rg2, and CK have been reported to inhibit adipogenesis or lipid accumulation through AMPK-associated signaling, while Rd acts through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway [38,39,40,41,42]. These findings indicate that suppression of adipocyte differentiation and lipid storage is a recurring metabolic action of ginseng-derived constituents; however, most studies rely on cellular or diet-induced obesity models, and direct molecular target validation remains limited.

2.1.4. Improvement of Glucose and Lipid Metabolism

Obesity is closely associated with type 2 diabetes mellitus (T2DM), and insulin resistance represents a major pathogenic link between these two conditions [43]. Several ginsenosides have been reported to improve these abnormalities through distinct metabolic signaling pathways. Rb2 enhances glucose metabolism by activating AKT signaling while suppressing tumor necrosis factor-alpha (TNF-α)-induced mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) activation [44], whereas Rg1 improves obesity-associated glucose disturbances through AMPK activation [45]. Rb1 also contributes to glycolipid metabolic regulation by upregulating PPARγ and aquaporin 7 (AQP7) expression [46]. In addition, ginsenoside Ro promotes glucagon-like peptide-1 secretion and increases energy expenditure through G protein–coupled bile acid receptor 5 (TGR5) activation [47]. Furthermore, (20R)-panaxadiol promotes the expression of thermogenic proteins through β2-adrenergic receptor-mediated the phosphorylation of cyclic AMP response element binding protein (CREB), leading to anti-obesity effects [48]. Collectively, these findings suggest that ginseng-derived constituents may improve obesity-related metabolic dysfunction through coordinated regulation of glucose utilization, lipid metabolism, and energy expenditure. However, most available evidence remains preclinical, and the relative contribution of these pathways to clinically meaningful metabolic improvement requires further validation (Table 1).

Table 1. Summary of ginseng-related interventions and their effects on obesity.

Treatment	Diseases	Inducer	Experimental Model	Dose/ Route	Duration	Primary Functional Outcomes	Mechanism/Evidence	Ref.
Rb1			3T3-L1 preadipocytes	10 μM	24 h	Promotes adipocyte browning	Regulates PPARγ	[21]
Rb2	Obesity	HFD	C57BL/6 J mice	40 mg/kg, intraperitoneal injection (i.p.)	10 days	Activates brown fat and promotes white fat browning	AMPK phosphorylation and thermogenic and mitochondrial genes	[22]
Shengmai San formula	Obesity	HFD	C57BL/6 J mice	2, 4, 8 g/kg, intragastric administration (i.g.)	6 weeks	Improves dyslipidemia and glucose metabolism; promotes adipose browning	Regulates intestinal flora and bile acid metabolism, promotes norepinephrine release in inguinal white adipose tissue	[24]
Ginseng polysaccharide	Obesity	HFD	C57BL/6 J mice	100 mg/kg, i.g.	8 weeks	Attenuates obesity and liver lipid accumulation	Regulates fecal microbiota and hepatic lysine degradation	[26]
Ginseng polysaccharide	Obesity	HFD	ICR mice	37, 75, 111 mg/kg, i.g.	30 days	Lowers blood lipid levels, improves lipid metabolism, inhibits liver fat accumulation, reduces intestinal inflammation	Increases the expression of tight junction proteins, regulates the intestinal microbiota	[27]
Ginsenosides	Obesity	HFD	SD rats	8, 40, 200 mg/kg, i.g.	30 days	Alleviates hepatic lipid metabolism	Modulates gut microbiota and the cholesterol metabolism signaling pathway	[29]
Rf	Obesity		3T3-L1 preadipocytes	10, 100 μM	8 days	Decreases the amount of lipid accumulated	PPARγ ↓, perilipin ↓	[31]
F2	Obesity		3T3-L1 cell line	10, 50, 100 μM	8 days	Inhibits adipogenesis	PPARγ ↓, perilipin ↓	[32]
Rc	Obesity		3T3-L1 preadipocytes	25, 50, 100 μM	6–12 days	Reduces intracellular triglyceride content and lipid accumulation	PPAR-γ ↓, C/EBP-α ↓	[33]
Rg5:Rk1	Obesity		3T3-L1 fibroblast	10, 100 µg/mL	8 days	Inhibits lipid droplet accumulation and decreases triglyceride content	STAT3/PPARγ/CEBPα signaling pathway ↓	[34]
Rg3	Obesity		3T3-L1 cells, Human Primary Pre-adipocytes Cell Culture, obese leptin-deficient mice	10, 30, 50, 100 µM; 10, 20, 30 µM; 0.1 mg/kg, i.g.	10days; 15 days; 8 weeks	Inhibits adipocyte differentiation and reduces adipogenic marker expression	PPAR-γ, C/EBP-α, FAS, and perilipin ↓	[36]
Rg3	HFD-induced hepatic steatosis		3T3-L1 pre-adipocyte cells, C57BL/6J mice	5, 25, 50 µM; 1 mg/kg, i.p.	3 or 9 days; 8 weeks	Reduces lipid accumulation and triglyceride levels; improves insulin sensitivity and hepatic steatosis	STAT5-PPARγ pathway ↓	[37]
Rg2	Obesity	HFD	3T3-L1 preadipocytes, KM mice	80 μM; 5, 10 mg/kg	8 days; 4 weeks	Anti- adipogenesis and anti-obesity	Activates AMPK pathway	[38]
Rg1	Obesity	HFD	Male KM mice, 3T3-L1 preadipocytes	10, 20 mg/kg, i.g.; 10, 20, 40 μM	4 weeks; 8 days	Decreases intracellular lipid content, adipocyte size, and adipose weight	PPARγ, C/EBPα, and sterol regulatory element binding protein 1c ↓, activates AMPK and inhibits acetyl-CoA carboxylase (ACC)	[39]
CK	Obesity		3T3-L1 adipocytes	10, 20, 30, 40 μM	8 days	Inhibits adipocyte differentiation	Activates AMPK and inhibits extracellular signal-regulated kinase (ERK)/p38 and AKT signaling pathways	[40]
Rd	Obesity	HFD	C57BL/6J mice	15 mg/kg/day, i.p.	23 days	Promotes thermogenesis and cold-induced white adipose tissue browning	Activates cAMP/PKA signaling and increases CREB phosphorylation	[41]
F2	Obesity	HFD	3T3-L1 preadipocytes, C57BL/6J mice	12.5, 25, 50, 100 μM; 50, 100 mg/kg, i.g.	8 days; 4 weeks	Decreases lipid accumulation, inhibits the expression of adipokines	Superoxide dismutase (SOD) and glutathione peroxidase ↓ the phosphorylation of ACC and AMPK ↑	[42]
Rb2	Obesity		C57BL/6 J mice; 3T3-L1 adipocytes	40 mg/kg, i.p.; 25 µM	10 days; 2 h	Reduces fat accumulation and improves glucose metabolism and insulin sensitivity	Activates AKT and inhibits TNF-α-induced MAPK/NF-κB signaling	[44]
Rg1	Obesity		C2C12 cells, C57BL/6 J mice	20, 40 µM; 300, 500 mg/kg/day, i.g.	12 h; 8 weeks	Improves obesity-related insulin resistance and glucose intolerance	Activates AMPK pathway	[45]
Rb1	Obesity	HFD	C57BL/6 mice, 3T3-L1 preadipocytes	40 mg/kg, i.p.; 40 µM	5 weeks; 24 h	Reduces body weight and improves glycolipid metabolism	Upregulates PPARγ and AQP7 protein levels.	[46]
Ro	Obesity	HFD	C57BL/6 J mice	45, 90 mg/kg, oral	8 weeks	Promotes glucagon-like peptide 1 secretion and energy expenditure	Activates TGR5	[47]
(20R)-panaxadiol	Obesity	HFD	C57BL/6 J mice	10 mg/kg, i.g.	5 weeks	Exerts anti-obesity effects	Activates β2-adrenergic receptor/CREB signaling and promotes thermogenic protein expression	[48]

Note: ↑ indicates upregulation or an increase, whereas ↓ indicates downregulation or a decrease.

2.2. Dyslipidemia

Dyslipidemia, commonly characterized by elevated triglycerides, reduced high-density lipoprotein cholesterol, and increased small dense low-density lipoprotein particles, is a major cardiometabolic risk factor and a key component of metabolic syndrome [49,50]. Current evidence suggests that Panax ginseng may improve lipid metabolism by reducing lipid accumulation, enhancing fatty acid oxidation, and regulating cholesterol and triglyceride metabolism [51]. These lipid-modulating effects may help limit the progression from metabolic dysfunction to atherosclerotic vascular injury, although the specific molecular targets and clinical relevance remain insufficiently defined.

2.3. Hypertension

Hypertension is a major cardiometabolic risk factor that interacts closely with obesity, insulin resistance, and dyslipidemia to accelerate cardiovascular injury [52]. Ginseng may contribute to blood pressure regulation by improving endothelial function, enhancing nitric oxide bioavailability, reducing oxidative stress, and modulating vascular inflammation. These vascular effects may help preserve endothelial homeostasis and limit the progression from cardiometabolic dysfunction to structural vascular damage [53]. However, the molecular targets responsible for these antihypertensive effects and their clinical relevance remain insufficiently defined.

3. Diabetic Cardiomyopathy

Diabetic cardiomyopathy represents an important cardiometabolic complication of diabetes, characterized by structural and functional myocardial abnormalities that develop independently of overt coronary artery disease, hypertension, or significant valvular disease [54]. The mechanisms underlying the decline in cardiac function in diabetic cardiomyopathy include increased fatty acids and cytokines, to adapt the diabetic hyperglycemic environment [55]. Ginseng has shown considerable potential in the treatment of diabetic cardiomyopathy, with several ginsenosides acting through distinct molecular pathways (Figure 2). Rb1 attenuates oxidative injury and abnormal ryanodine receptor 2 (RyR2) phosphorylation linking ginseng-derived constituents to the regulation of myocardial calcium homeostasis [56]. Another study suggests that Rh2 may activate PPARδ to inhibit fibronectin expression levels, thereby improving hyperglycemia-induced cardiac dysfunction and fibrosis [57]. Beyond isolated ginsenosides, formulas containing ginseng also demonstrate beneficial effects in treating diabetic cardiomyopathy. For example, Shengmai San improves diabetic cardiomyopathy by enhancing mitochondrial lipid metabolism [58]. Overall, current evidence suggest that ginseng and its active constituents may alleviate diabetic cardiomyopathy by improving metabolic dysregulation, reducing oxidative stress, modulating calcium handling, and attenuating myocardial fibrosis. However, its direct target validation remains limited to a small number of studies, and most evidence is still preclinical.

Figure 2. Mechanisms associated with the cardioprotective effects of ginseng-related interventions in diabetic cardiomyopathy. Diabetic cardiomyopathy is associated with hyperglycemia, lipid metabolic disorder, oxidative stress, inflammation, and calcium-handling dysfunction, leading to impaired cardiac structure and function. Ginseng and its active constituents, including Rg3, Rb1, Rh2, and Shengmai San, exert protective effects by improving metabolic homeostasis, reducing oxidative stress and inflammation, regulating RyR2 activity and Ca²⁺ handling, and enhancing mitochondrial and cardiac energy metabolism. Collectively, these actions attenuate fibrosis, apoptosis, and cardiac dysfunction, thereby slowing the progression of diabetic cardiomyopathy. ↑ indicates upregulation or an increase, whereas ↓ indicates downregulation or a decrease. The different arrow styles are used solely for visual presentation and have no specific biological significance. This figure was created by the authors based on a synthesis of the existing literature.

4. Atherosclerosis

Metabolic syndrome comprises multiple metabolic risk factors that increase susceptibility to atherosclerosis [59]. Atherosclerosis is a chronic pathological process characterized by lipid accumulation and plaque formation within the arterial wall. It forms the common pathological basis for numerous cardiovascular conditions, representing a major public health concern worldwide [60]. Atherosclerotic lesions develop slowly over many years, and may eventually impair blood flow, leading to the symptoms of stable angina or claudication [61]. Numerous well-documented risk factors are associated with atherosclerosis, including hypertension, dyslipidemia, advanced age, and smoking [62]. Ginseng and its various active components may exert anti-atherosclerotic effects through multiple mechanisms (Figure 3).

Figure 3. Anti-atherosclerotic effects of ginseng-related interventions and their associated mechanisms. Ginseng and its active constituents exert anti-atherosclerotic effects through antioxidative, endothelial-protective, anti-inflammatory, immunomodulatory, and metabolic regulatory actions. These effects involve improvement of endothelial function, modulation of macrophage polarization and cytokine release, regulation of gut microbiota and host metabolic homeostasis, and inhibition of foam cell formation, lipid accumulation, vascular cell proliferation, and plaque instability. ↑ indicates upregulation or an increase, whereas ↓ indicates downregulation or a decrease. The different arrow styles are used solely for visual presentation and have no specific biological significance. This figure was created by the authors based on a synthesis of the existing literature.

4.1. Anti-Oxidant Effects and Protection of Vascular Endothelial Function

Vascular endothelial cells (VECs) play a critical role in the occurrence and progression of atherosclerosis [63]. Exposed directly to blood, VECs lining blood vessels can become dysfunctional and inflamed when triggered by risk factors such as hypercholesterolemia, diabetes, hypertension, smoking, and ageing. These pathological changes are key early drivers of atherosclerosis, particularly in regions where blood flow is disturbed [64]. Reactive oxygen species (ROS) refer to reactive chemical species derived from molecular oxygen (O₂) that exhibit greater chemical reactivity than O₂ itself. This group encompasses both radical species, such as the superoxide anion (O₂⁻) and the hydroxyl radical (HO•), and non-radical molecules such as hydrogen peroxide (H₂O₂) [65]. Although ROS are generated as by-products of normal aerobic metabolism, their levels can become elevated under various pathological or stressful conditions, which constitutes a fundamental mechanism of cellular and tissue damage [66]. During atherosclerosis, excessive ROS generation coupled with a downregulation of antioxidant defenses leads to an imbalance that culminates in oxidative stress [67].

Active components of ginseng may counteract these pathological processes through multiple mechanisms. Ginseng oligopeptide extract protects human aortic endothelial cells against nicotine-induced oxidative injury by modulating cellular antioxidant defenses and regulating the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived 2-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway [68]. Rb1 also attenuates resistin-induced oxidative stress and dysfunction in human coronary artery smooth muscle cells by reducing ROS generation and enhancing SOD activity [69]. In addition, Rb1 inhibits vascular calcification, a pathological process closely associated with atherosclerotic progression [70].

Endothelial cell senescence may also contribute to atherogenesis [71]. In this context, Rb2 targets microRNA-216a (miR-216a) and exerts anti-inflammatory effects, thereby alleviating endothelial cell senescence [72]. Rb3 similarly protects human aortic endothelial cells against oxidized low-density lipoprotein (ox-LDL)-induced injury by reducing oxidative stress, inflammation, and endothelial dysfunction [73]. Similarly, ginsenoside Rg3 has been reported to alleviate ox-LDL-induced endothelial dysfunction and attenuate atherosclerosis in ApoE^−/− mice through regulation of the PPARγ/FAK signaling pathway. Pharmacological inhibition with GW9662 further supported the involvement of PPARγ in these protective effects [74]. Additionally, Tongxinluo, a traditional Chinese medicine, has also demonstrated protective effects for myocardial infarction [75], and mitigates atherosclerosis by suppressing ROS/NOD-like receptor family pyrin domain-containing 3 (NLRP3)/caspase-1-mediated endothelial cell pyroptosis [76]. Collectively, these findings suggest that preservation of endothelial redox homeostasis may represent an important component of the anti-atherosclerotic actions of ginseng-derived constituents, although most available evidence remains preclinical and direct target validation is still limited.

4.2. Anti-Inflammatory and Immunomodulatory Effects

Atherosclerosis is a multifactorial process in which the immune system plays a key role, both systemically in the circulation and locally at vascular lesion sites [77]. Over the past two decades, atherosclerosis has become widely recognized as a chronic inflammatory disease, and the detrimental role of inflammation in its pathophysiology is now well established [78]. Several ginsenosides have been reported to modulate these inflammatory and immune responses. For instance, Rb2 attenuates atherosclerotic plaque formation, lipid accumulation, and M1 macrophage polarization through the targeted inhibition of miR-216a [79]. In contrast, 20(S)-Rg3 promotes PPARγ-dependent M2 macrophage polarization, suggesting therapeutic potential in diabetic atherosclerosis [80]. Beyond macrophages, Rg2 attenuates carotid intimal hyperplasia following balloon injury in rats by suppressing phenotypic transformation of vascular smooth muscle cells (VSMCs), thereby mitigating the associated inflammatory response [81]. A similar anti-inflammatory effect has been reported for the Shen-Hong-Tong-Luo formula, a multi-herbal preparation containing ginseng, through activation of the PPARγ/LXRα/ABCA1 pathway. However, the contribution of ginseng itself cannot be isolated from that of the other herbal components [82].

4.3. Regulation of Intestinal Flora and Metabolic Homeostasis

Alterations in the composition and function of gut microbiota contribute to the pathogenesis of various diseases, including cardiovascular disease [83]. The gut microbiota and its metabolites influence the pathogenesis of atherosclerosis throughout its development, from the initial engagement of endothelial cells and macrophages, through the intermediate involvement of VSMCs, to the advanced phase involving adaptive immune cells such as T cells, B cells, and dendritic cells [84]. Accordingly, targeting the “gut-heart axis” has emerged as a promising therapeutic strategy.

Ginseng and its compounds show significant potential. Total ginseng saponin extract and Rb1/Rg1 combinations retard atherogenesis via remodeling host–microbiome metabolic homeostasis [85]. In HFD-induced ApoE^−/− mice, Rc also ameliorates atherosclerotic injury by regulating both microbial and host metabolomic profiles [86]. These findings suggest that microbiota-dependent metabolic regulation may contribute to the anti-atherosclerotic effects of ginseng-derived constituents. However, the specific microbial metabolites, host receptors, and downstream molecular targets responsible for these effects remain incompletely defined. Similar effects have been reported for ginseng-containing multi-herbal preparations. Ginsenosides from Sheng-Mai Yin (SMY) exert therapeutic effects against atherosclerosis through the maintenance of lipid homeostasis through regulation of cholesterol and lysophosphatidylcholines [87]. Furthermore, Tongxinluo, a multi-target traditional Chinese medicine formula, improves atherosclerotic plaque stability and reduces inflammation in rabbits by modulating intestinal flora and host metabolism [88]. Because both are multi-component formulations, these effects cannot be attributed specifically to ginseng alone.

4.4. Lipid Handling and Vascular Remodeling

Disordered lipid metabolism is one of the major mechanisms driving atherosclerosis [89]. Evidence suggests that Rb1 reduces lipid accumulation and foam cell formation in vascular smooth muscle cells and attenuates atherosclerotic plaque development [90]. Furthermore, Rb1 suppresses vascular cell proliferation by inhibiting the interaction between cyclin D and cyclin-dependent kinase 4, which may represent another mechanism underlying its anti-atherosclerotic effects [91]. Similar anti-atherosclerotic effects have also been reported for the Huxin formula and Baoyuan decoction, which reduce lipid accumulation and inflammation and suppress foam cell formation [92]. Taken together, current evidence indicates that ginseng and its active constituents may attenuate atherosclerosis through antioxidative and endothelial-protective effects, anti-inflammatory and immunomodulatory actions, regulation of gut microbiota and metabolic homeostasis, and improvement of lipid metabolism and vascular remodeling.

5. Myocardial Infarction and Myocardial Ischemia/Reperfusion Injury

Myocardial infarction (MI) is a pathological state caused by coronary artery ischemia, which leads to insufficient blood perfusion of the myocardium [93]. Regarding myocardial infarction, timely and effective revascularization can preserve contractile myocardial tissue, reduce the infarct area, and improve clinical outcomes. However, the reperfusion may lead to a further aggravation and acceleration of myocardial damage, which is known as myocardial ischemia/reperfusion (MI/R) injury [94]. A variety of drugs, including exenatide, cyclosporine A, and aspirin, have been reported to improve prognosis; however, their use is limited by low targeting specificity and potential adverse effects [95]. A large number of studies have shown that ginseng and its active ingredients, along with compound preparations, intervene in this process through multiple targets, providing a promising multi-dimensional therapeutic strategy for the prevention and treatment of MI/R injury (Figure 4).

Figure 4. Cardioprotective effects of ginseng-related interventions and their associated mechanisms in myocardial infarction and ischemia/reperfusion injury. Ginseng and its active constituents protect against MI and MIR injury by regulating cell death, suppressing oxidative stress and inflammation, improving mitochondrial function and energy metabolism, modulating autophagy, and promoting angiogenesis, thereby reducing myocardial injury and facilitating cardiac repair. ↑ indicates upregulation or an increase, whereas ↓ indicates downregulation or a decrease. The different arrow styles are used solely for visual presentation and have no specific biological significance. This figure was created by the authors based on a synthesis of the existing literature.

5.1. Regulation of Cell Death: Apoptosis, Pyroptosis, and Ferroptosis

Cell death serves dual essential functions: it shapes the organism by supporting morphogenesis during development and protects the organism by maintaining homeostasis through the removal of unwanted cells after birth [96]. Multiple forms of regulated cell death have been identified, including apoptosis, autophagy-associated cell death, cornification, pyroptosis, and ferroptosis [97]. Pyroptosis is commonly initiated by inflammasome-forming pattern recognition receptors, particularly NOD-like receptors, while other PRR families, including Toll-like receptors and C-type lectin receptors, can contribute to upstream inflammatory priming and innate immune activation [98]. Under myocardial ischemia and hypoxia, toll-like receptor 4 (TLR4) activation induces NF-κB p65 activation, which further triggers the activation of the NLRP3 inflammasome and subsequent caspase-1 activation [99]. Notably, Rh2 effectively inhibits cardiomyocyte pyroptosis by downregulating key pyroptosis-related proteins, including NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 [100]. Apoptosis is a highly regulated, energy-dependent form of programmed cell death that is initiated and executed through specific signaling cascades [101]. It is integral to key physiological processes such as embryogenesis, tissue homeostasis, and aging. However, excessive apoptotic cell death constitutes a major pathogenic process in acute MI-related myocardial injury [102]. Several ginseng-derived compounds and ginseng-containing traditional formulas have demonstrated marked anti-apoptotic effects. Syringaresinol [103], Renshen Yangrong decoction [104], and Zhi-Gan-Cao-Tang [105] have all been shown to protect cardiomyocytes against apoptosis. Ginsenoside Rg3 improves cardiac function after MI/R injury by reducing apoptotic cell death by inhibiting caspase-3 activation [106]. In addition, 25-hydroxyl-protopanaxatriol, a novel triterpenoid from ginseng stems and leaves [107], inhibits H₂O₂-induced injury in H9c2 cardiomyocytes by activating the PI3K/AKT signaling pathway [108]. In H9c2 cells, Rb1 inhibits the mitochondrial apoptotic pathway, as evidenced by reduced cytochrome c release and decreased levels of cleaved caspase-3, ultimately leading to cardiomyocyte protection [109]. Similarly, Rb2 and Rb3 have been reported to suppress cardiomyocyte apoptosis in rat models [110]. Zenglv Fumai granule, a clinical prescription for treating sick sinus syndrome, a condition associated with MI/R injury, also attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by regulating the tripartite interaction motif 28/glutathione peroxidase 1/ROS pathway [111]. Ferroptosis is a distinct form of regulated cell death characterized by iron accumulation and lipid peroxidation [112]. Ginsenoside Re has been shown to attenuate MI/R-induced ferroptosis by targeting the miR-144-3p/solute carrier family 7-member 11 axis [113]. Ginsenoside Rg3 has been shown to regulate the Keap1/Nrf2/glutathione peroxidase 4 (GPX4) signaling pathway, offering protection against ferroptosis [114]. Similarly, the clinical formulation Shenmai injection (SMI) confers protection against MI/R injury by activating the protective Nrf2/GPX4-associated signaling pathway and suppressing ferroptotic injury [115]. Collectively, these findings suggest that ginseng-derived constituents may protect the ischemic myocardium by modulating multiple forms of regulated cell death, including pyroptosis, apoptosis, and ferroptosis. Nevertheless, most available evidence remains based on pathway-level regulation, and direct molecular target validation is still limited.

5.2. Attenuation of Oxidative Stress and Inflammatory Responses

Oxidative stress, characterized by an imbalance between excessive ROS production and deficient antioxidant capacity, is a pivotal pathophysiological mechanism in MI/R injury. The interaction between ROS and inflammation forms a deleterious feed-forward loop in MI/R injury. ROS activate inflammatory signaling cascades, while inflammatory mediators further enhance ROS generation, thereby aggravating oxidative damage [116]. Given this interconnected pathophysiology, attenuation of oxidative stress and inflammation represents a key cardioprotective mechanism.

Extensive studies have shown that ginseng and its bioactive components exert effective antioxidant and anti-inflammatory effects by regulating multiple molecular pathways. Ginseng extract exerts anti-oxidant effects by activating Nrf2 and down-regulating NF-κB, protein kinase C, angiotensin II type 1 receptor, and inducible nitric oxide synthase, thereby protecting the heart against injury [117]. F2 ameliorates MI by mitigating cardiomyocyte apoptosis, oxidative stress, and mitochondrial dysfunction through the activation of both the Nrf2/HO-1 and PI3K/AKT signaling pathways [118]. Sirtuin 1 (SIRT1), a highly conserved oxidized nicotinamide adenine dinucleotide dependent deacetylase [119], is involved in the regulation of cellular energy metabolism, aging, and oxidative stress-related transcription [120]. Both 20(S)-ginsenoside Rg2 and ginsenoside Rb2 act as SIRT1 activators, reducing oxidative stress and inflammation to protect against MI/R injury [121,122]. Ginsenosides Rc [123,124] and Rh2 also exert antioxidant and anti-inflammatory effects. Notably, the effect of Rc is achieved by activating SIRT1, whereas Rh2 acts through the Nrf2/HO-1/NLRP3 signaling pathway [125]. These findings identify SIRT1 and Nrf2-related signaling as recurrent regulatory nodes in the antioxidant and anti-inflammatory actions of ginseng-derived constituents. Evidence from ginseng-containing preparations further supports these effects. SMI has been reported to attenuate MI/R injury, at least partly through suppression of oxidative stress [126]. Similarly, Shenxian-Shengmai oral liquid may attenuate oxidative injury in cardiomyocytes, with myocardial SOD1 and glutamate cysteine ligase catalytic subunit identified as potential therapeutic targets [127]. By inhibiting the K27 ubiquitination of absent in melanoma 2 (AIM2), SMY suppresses AIM2 inflammasome activation following MI/R injury, ultimately reducing inflammation and attenuating tissue damage [128]. Overall, these findings highlight oxidative–inflammatory coupling as an important mechanism underlying the cardioprotective effects of ginseng-derived constituents in MI/R injury.

5.3. Improvement of Mitochondrial Function and Energy Metabolism

During acute ischemia/reperfusion injury, mitochondrial dysfunction critically exacerbates cellular demise, determining the extent of injury in acute MI [129]. Ras homolog family (Rho) kinase plays a key role in MI/R injury [130]. Rb1 regulates energy metabolism by modulating RhoA signaling pathways, thereby alleviating the myocardial damage induced by I/R [131]. Ginseng polysaccharides protect H9c2 cells from MI/R injury through mechanisms involving mitochondrial metabolism and the reperfusion injury salvage kinase pathway [132]. Mitochondrial biogenesis and homeostasis also appear to be important targets of ginseng-derived constituents. Rd protects against myocardial ischemic injury through regulation of the Wnt family member 5A (WNT5A)/Ca²⁺ pathway, accompanied by enhanced mitochondrial biogenesis [133]. Recent evidence has further linked ginsenoside Rd to metabolic reprogramming in MI/R injury. Rd was reported to promote cardiac regeneration through a PPARG/3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2)-associated mechanism involving ketone body metabolism, highlighting a potential link between metabolic regulation and myocardial repair following ischemia/reperfusion injury [134]. Sirtuin 3 (SIRT3) is a critical mitochondrial deacetylase involved in regulating mitochondrial homeostasis and modulating autophagy. Ginsenoside Rk1, a rare saponin derived from heat-processed ginseng, alleviates MI/R injury and improves mitochondrial function by regulating SIRT3 [135]. These findings suggest that preservation of mitochondrial quality and metabolic capacity may represent an important component of ginseng-mediated cardioprotection. Ginseng-containing preparations have shown similar effects. SMI exerts protective effects on cardiomyocytes through the regulation of mitochondrial dynamics, autophagy [136], and energy metabolism [137]. Xinmai’an tablets have also been reported to attenuate myocardial injury by activating the AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling pathway and reducing mitochondrial oxidative stress [138].

5.4. Modulation of Autophagy

Autophagy is a lysosome-dependent intracellular degradation process that maintains cellular homeostasis by degrading damaged proteins and organelles [139]. Ginsenoside Rg3 enhances autophagy through the AMPK signaling pathway and attenuates MI-induced cardiac dysfunction [140]. In contrast, CK confers protection against I/R injury in H9c2 cells by suppressing detrimental autophagy and apoptosis through PI3K/AKT activation. These findings suggest that the cardioprotective effect of ginseng may depend on context-specific modulation of autophagy rather than uniform activation or inhibition of autophagy [141]. Daming capsule, a traditional Chinese medicine preparation, improves cardiac function after MI through activation of the SIRT1/AMPK pathway and enhancement of nucleotide-binding oligomerization domain-like receptor family member X1-mediated mitophagy [142].

5.5. Promotion of Angiogenesis

Therapeutic promotion of angiogenesis has gained attention as a strategy to enhance neovascularization and tissue recovery following MI [143]. Beyond direct cellular protection, angiogenesis represents another mechanism underlying the cardioprotective effects of ginseng components and compound preparations. For instance, ShenZhuGuanXin granules promote myocardial angiogenesis in rat models of MI by up-regulating the expression of platelet endothelial cell adhesion molecule 1/CD31 and vascular endothelial growth factor (VEGF) [144]. Similarly, Shensong Yangxin capsule ameliorates the impaired myocardial microcirculation following MI by balancing endothelial-derived vasodilators and vasoconstrictors and up-regulating the expression of VEGF and endothelial nitric oxide synthase (eNOS) [145]. Moreover, ginsenoside Rh2 promotes angiogenesis via the ERK signaling pathway, thereby contributing to the mitigation of acute MI [146]. Together, these findings suggest that enhancement of neovascularization and microvascular function may complement the direct myocardial protective effects of ginseng-related interventions after MI.

6. Cardiomyocyte Hypertrophy and Remodeling

Cardiomyocyte hypertrophy is a compensatory thickening of the muscle in response to elevated left ventricular (LV) wall stress [147]. Cardiac hypertrophy serves initially as an adaptive and compensatory mechanism to maintain cardiac output under stress. However, sustained stress can drive this response toward pathological remodeling and eventually heart failure [148]. Increasing evidence suggests that ginseng-derived constituents may modulate this transition through multiple mechanisms, including regulation of oxidative stress and inflammation, metabolic homeostasis, regulated cell death, and vascular signaling.

6.1. Mitigation of Inflammation and Oxidative Stress

Inflammation and oxidative stress are important contributors to the development and progression of pathological cardiac remodeling [149]. Maintaining a tight balance between ROS generation and clearance is critical for cardiovascular health, as its dysregulation is a key driver of cardiovascular disease [150]. Ginsenoside Rg3 has been demonstrated to ameliorate angiotensin II-induced hypertrophy in human cardiomyocytes by repressing the NLRP3 inflammasome and alleviating oxidative stress, an effect mediated through the modulation of the SIRT1/NF-κB pathway [151]. Together, these findings suggest that coordinated regulation of oxidative and inflammatory signaling may contribute to the anti-remodeling effects of ginsenosides.

6.2. Restoration of Metabolic Homeostasis

The myocardium regulates the energy supply in order to maintain the function of supplying oxygen and nutrients to the heart [152]. Therefore, therapeutic strategies aimed at restoring metabolic flexibility and energy homeostasis hold significant promise. Ginsenoside Rg3 exerts a protective effect by inhibiting the acyltransferase activity of histone acetyltransferase P300, reducing the 2-hydroxyisobutyrylation of mitochondrial enzyme dihydrolipoamide dehydrogenase (DLD) and subsequently restoring the activity of pyruvate dehydrogenase, a key gatekeeper of glucose oxidation [153]. This P300–DLD–pyruvate dehydrogenase (PDH) regulatory axis provides a comparatively detailed mechanistic link between ginsenoside-mediated post-translational regulation and myocardial energy metabolism. AMPK is a heterotrimeric complex comprising a catalytic α subunit and two regulatory subunits β and γ subunits. This conserved structure is fundamental to its role as a central cellular energy sensor and master regulator of metabolic homeostasis [154]. SMI suppresses cardiomyocyte hypertrophy and apoptosis by activating the AMPK signaling pathway via energy-dependent mechanisms [155]. By inhibiting the hypoxia-inducible factor 1-alpha (HIF-1α)/PPAR signaling pathway, SMY consequently activates the PKA pathway, thereby improving energy metabolism disorder in a rat model of myocardial hypertrophy [156].

6.3. Regulation of Cell Death

Increased ferroptosis has been observed in cardiovascular diseases, including cardiac hypertrophy [157]. In a model of doxorubicin-induced acute cardiotoxicity, Rb1 exerts protective effects by suppressing both autophagy and ferroptosis. Specifically, autophagy inhibition is mediated via the AMPK pathway, while ferroptosis suppression occurs through the Nrf2 pathway [158]. Although this evidence is derived from a cardiotoxicity model rather than a direct model of cardiac hypertrophy, it suggests that modulation of regulated cell death may represent an additional mechanism through which Rb1 influences pathological cardiac remodeling.

6.4. Vasodilation and Nitric Oxide Signaling

Beyond direct actions on cardiomyocytes, ginsenoside Rg1 protects abdominal aorta coarctation induced LV hypertrophy, with its effects being mediated, at least in part, by the production and release of endogenous nitric oxide, a potent vasodilator with important cardiovascular protective functions [159]. These findings suggest that improvement of vascular function and NO signaling may contribute to the anti-remodeling effects of Rg1 under conditions of increased cardiac afterload.

7. Heart Failure

As a significant public health challenge, heart failure (HF) affects over 56 million individuals globally, with an estimated prevalence of 1–2% [160]. HF is a complex clinical syndrome manifested by typical symptoms and signs, arising from any structural or functional impairment that affects ventricular filling or blood ejection [161]. The factors influencing HF are classified into three types, non-modifiable risk factors including age, sex and genetic variants, patient-specific modifiable risk factors, such as smoking, lack of physical activity, unhealthy diet, excessive alcohol consumption, stress and socioeconomic disadvantage; and medically modifiable risk factors, including hypertension, obesity, hyperlipidaemia, diabetes mellitus, atrial fibrillation, sleep apnoea, worsening renal function, hypertensive disorders of pregnancy, chronic obstructive pulmonary disease and chronic kidney disease [160]. Accumulating evidence suggests that Panax ginseng and its bioactive constituents may influence HF progression through multiple mechanisms involving energy metabolism, mitochondrial homeostasis, autophagy and mitophagy, oxidative stress, inflammation, and pathological remodeling.

7.1. Amelioration of Energy Metabolic Disorders

Energy deficiency is a characteristic of HF, primarily attributed to a decrease in mitochondrial oxidative capacity [162]. Increasing evidence suggests that ginseng-derived active components and formulas exert therapeutic effects on HF by regulating energy metabolism. The PI3K/AKT and AMPK signaling pathways are closely associated with energy metabolism [163]. Ginseng extract exerts therapeutic effects against HF, primarily via the PI3K/AKT and AMPK pathways, with consequent improvement in energy metabolism [164]. After the early compensatory remodeling stage, the phosphorylation of AMPK may inhibit MAPKs activation, YiQiFuMai powder injection ameliorates cardiac remodeling and HF, at least in part, through the inhibition of the MAPKs signaling pathways [165]. By activating the upstream PPARα regulator, Rb3 inhibits mitochondria-mediated apoptosis and enhances energy metabolism to exert cardioprotective effects [166]. In both in vivo HF models and in vitro hypoxia/ischemia models, Xinfuli Granule, an enhanced derivative of Baoyuan decoction, mitigates mitochondrial injury, inhibits endoplasmic reticulum stress, and improves energy production through the RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) pathway [167]. In addition, ginsenoside Rd [168] and total secondary ginsenosides [169] promote mitochondrial biogenesis, thereby increasing adenosine triphosphate (ATP) production and improving cardiac function. A study reveals a novel mechanism by which Rb1 restores cardiac energy homeostasis by regulating the Fas-associated death domain (FADD)/PPAR α axis, further establishing its cardioprotective potential in HF [170].

7.2. Regulation of Autophagy and Mitophagy

Autophagy is regarded as a new biomarker of HF [171]. One study demonstrated that autophagy plays a detrimental role in the transition from myocardial hypertrophy to HF [172]. Ginseng could enhance the effect of metoprolol in chronic HF; the mechanism is connected with inhibiting autophagy [173]. Mitophagy may also contribute to the regulation of mitochondrial quality during cardiac remodeling. Rg1 demonstrates significant efficacy in alleviating MI-induced cardiac remodeling in mice, a key precursor to HF. Mechanistically, it promotes mitophagosome formation, alleviates cardiac mitochondrial damage, and enhances SIRT1/PINK1/Parkin-mediated mitophagy. Its protective role was further confirmed in H₂O₂-treated H9c2 cells, where it activates the SIRT1/PINK1/Parkin pathway, leading to increased cell viability and reduced apoptosis and fibrosis [174]. These findings link Rg1-mediated mitophagy to preservation of mitochondrial homeostasis during pathological cardiac remodeling. By scavenging ROS, Yang-Xin-Xue-Ke-Li, a primary traditional Chinese Medicine for cardiovascular diseases, inhibits DOX-induced autophagy and mitophagy to exert its therapeutic effects [175]. 20S-O-Glc-DM is a derivative developed to address the low bioavailability of natural ginsenosides [176]. In models of LV diastolic dysfunction in mouse models and isoproterenol (ISO)-induced H9c2, excessive autophagy is reduced by 20S-O-Glc-DM, which is mediated through the AMPK- mechanistic target of rapamycin (mTOR)- unc-51-like autophagy activating kinase 1 (ULK1) pathways [177]. In contrast, Shexiang Baoxin pill alleviates MI/R injury by activating autophagy via a competing endogenous RNAs mechanism targeting the Map3k8 signaling pathway [178]. Together, these apparently divergent findings indicate that restoration of appropriate autophagic activity, rather than unidirectional activation or inhibition, may be important for cardioprotection.

7.3. Regulation of Cell Survival and Apoptosis Pathways

Apoptotic cell death participates in the process of subsequent LV remodeling and the development of HF [102]. Several ginseng-containing traditional formulations have been reported to preserve cardiomyocyte survival by regulating apoptosis-related signaling. Shenfu Formula, a classic traditional Chinese medicine, inhibits apoptosis through modulation of Fas/FasL and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) signaling pathway to suppress apoptosis. Which effectively improves cardiac function in rats with HF [179]. Baoyuan decoction, a formula that has been applied for the treatment of cardiovascular diseases clinically for decades, inhibits apoptosis, through regulating the angiotensin type 1 receptor (AT1)-cardiac ankyrin repeat protein (CARP) signaling pathway, thereby improves cardiac function and protects cardiomyocytes from injury. Its active ingredients include ginsenoside Rg3, Rb1, Rc and Re [180]. Integrated network pharmacology and experimental validation demonstrate that Fuzheng Yangxin recipe improves cardiac function through a mechanism involving the regulation of STAT3 expression and inhibition of apoptosis [181]. Xin Fu Kang, a traditional formula designed to alleviate chronic HF, preserves mitochondrial function and inhibits apoptosis by regulating nuclear receptor subfamily 4 group A member 1-mediated functional interaction between endoplasmic reticulum and mitochondria in cardiomyocytes [182]. Shen’ge formula, which holds a significant position in the treatment of heart diseases, has been shown in clinical studies to effectively alleviate the clinical symptoms of patients with HF [183] while experimental evidence suggests that it regulates the AKT/HIF-1α/p53 pathway to suppress cardiac hypertrophy and apoptosis and to promote angiogenesis [184]. Sheng-Mai-San attenuates MI-induced HF by regulating Ca²⁺ homeostasis and suppressing mitochondrial mediated apoptosis through the modulation of Ca²⁺-calcineurin-mediated Drp1 signaling pathways [185]. Similarly, Jin-Xin-Kang exerts a protective effect against HF through the amelioration of mitochondrial dysfunction, achieved by modulating the calcineurin/Drp1 signaling pathway [186].

7.4. Modulation of Inflammatory Responses

Inflammation plays a crucial role in the progression of HF [187]. The main function of the inflammatory response is to address myocardial damage, enabling the heart to adapt to abnormal conditions in the short term and restore internal balance and cardiovascular function in the long term. However, if this abnormal state persists, the continuous inflammatory state within the tissues could have adverse effects on myocardial cells and extracellular matrix, leading to progressive LV remodeling and dysfunction, ultimately resulting in HF due to poor adaptation [188]. In an angiotensin II (Ang II)-induced hypertensive HF model, both ginsenoside Rg5 [189] and 20(S)-ginsenoside Rh2 [190] demonstrates protective effects, and the mechanism involves inhibition of the c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) pathway. These findings suggest that the suppression of maladaptive inflammatory signaling may contribute to the protective effects of individual ginsenosides in HF. Xin-Li formula, with ginseng serving as the minister herb, has demonstrated marked protective effects against MI-induced HF in rats. Mechanistically, these effects are achieved through Treg immunomodulation and the NLRP3 inflammasome inhibition [191]. Moreover, in rats with ISO-induced HF, Shenfu injection effectively modulates inflammatory imbalance, reduces serum and urine Trimethylamine N-oxide (TMAO) levels, and improves gut microbiota composition, thereby alleviating cardiac injury [192]. Huoxin pill, a traditional Chinese medicine formula that has shown significant efficacy in treating chronic HF [193], exerts therapeutic effects in verapamil-induced zebrafish models by inhibiting oxidative stress-triggered inflammation and apoptosis [194].

7.5. Regulation of Gut Microbiota

Emerging evidence suggests that gut microbiota dysbiosis drives the onset and progression of cardiometabolic diseases by disrupting systemic metabolism and homeostasis [195]. In HF, the modulation of gut microbiota has therefore emerged as a promising therapeutic strategy. The therapeutic effect of C20DM on HF is mediated by gut microbiota modulation, enhanced microbial diversity, upregulation of tight junction proteins including occludin, claudin, and zonula occludens-1, and subsequent inhibition of the TLR4- myeloid differentiation primary response 88 -NF-κB pathway [196]. Qiliqiangxin, a well-known compound preparation containing ginseng, has been used to treat HF for over a decade. It exerts its therapeutic effects, at least in part, by modulating the gut microbiota and inhibiting the NLRP3 inflammasome, thereby alleviating ventricular remodeling in rats [197]. Shenfu Injection ameliorates cardiac energy metabolism and intestinal integrity in HF rats, effects mediated by the modulation of gut microbiota, specifically an enrichment of short-chain fatty acid (SCFA)-producing Akkermansia and Blautia [198]. Dengzhanshengmai (DZSM) capsule, a traditional Chinese medicine preparation, is widely used to treat CVDs [199]. A study demonstrated that in HF, DZSM improves intestinal barrier function. This effect was associated with a decreased relative abundance of Turicibacter and Turicibacter_sp_TS3, and the regulation of genes encoding enzymes involved in phenylacetylglutamine synthesis [200]. These findings suggest that modulation of microbial composition, intestinal barrier function, and microbiota-derived metabolic signaling may contribute to the cardiovascular effects of ginseng-related interventions in HF.

7.6. Regulation of Calcium Homeostasis and Fibrotic Remodeling

Sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2A (SERCA2a), a key transporter regulating sarcoplasmic reticulum Ca²⁺ influx [201], is an important factor that regulates endoplasmic reticulum (ER) function in cardiovascular diseases. It has been demonstrated that Rg3 has a positive effect on the abnormal Ca²⁺ cycle in the cardiomyocytes of mice with HF, which is related to its regulation of SERCA2a small ubiquitin-like modifier (SUMO)ylation [202]. In addition, the disruption of transforming growth factor (TGF-β)1 pathway has been implicated in several human diseases, including myocardial fibrosis [203], and Smad3 is essential for TGF-β1-induced gene expression [204]. Studies have shown that ginsenoside Re alleviates isoproterenol-induced myocardial fibrosis and HF in rats, an effect associated with the modulation of the TGF-β1/Smad3 signaling pathway [205]. Similarly, Qiliqiangxin attenuates cardiac remodeling in doxorubicin-induced HF rats by inhibiting of TGF-β1/Smad3 [206]. Further relevant information is documented in Table 2.

Table 2. Summary of ginseng-related interventions and their effects on heart failure.

Treatment	Diseases	Inducer	Experimental Model	Dose/Route	Duration	Primary Functional Outcomes	Mechanism/Evidence	Ref.
Ginseng	Heart failure	ISO	SD rats	1.5, 3.0, 4.5 g/kg, (route not specified)	3 weeks	Reduces myocardial injury and improves cardiac function and energy metabolism	Activates PI3K/AKT and AMPK signaling pathways	[164]
YiQiFuMai powder	Myocardial remodeling and heart failure	CAL	ICR mice	0.13, 0.26, 0.53 g/kg, i.p.	2 weeks	Improves cardiac function, attenuates structure damage, oxidative stress, necrosis, collagen deposition, and fibrosis	Inhibits MAPKs signaling pathway	[165]
Rb3	Heart failure	LAD, OGD/R	C57BL/6J mice, H9C2	0.63 mg/kg; 40 μM	7 days; 20 h	Improves cardiac function, fatty acid oxidation, and mitochondrial integrity; reduces cardiomyocyte apoptosis	Upregulates PPARα, carnitine palmitoyltransterase-1α, acyl-CoA dehydrogenase long chain, and SIRT3; PPARα inhibition abolishes the metabolic and anti-apoptotic effects	[166]
Xinfuli granule	Heart failure	LAD, hypoxia-ischemia	SD rats, H9c2	50, 100, 200 mg/kg, i.g.; 1, 2, 4 mg/L	4 weeks; 24 h	Improves energy production by alleviating mitochondrial injury	Downregulates activating transcription factor 4, C/EBP homologous protein (CHOP), p- eukaryotic translation initiation factor 2 alpha, and p- protein kinase R-like endoplasmic reticulum kinase; suppresses RhoA/ROCK signaling	[167]
Rd	Heart failure	TAC, CAL, ISO, OGD	C57BL/6J mice, H9c2	5, 10, 20 mg/kg, i.g. 20 μM	4 weeks 2 weeks 1 week	Ameliorates myocardial ischemia injury and improves mitochondrial biogenesis	Inhibits WNT5A/Ca2+ signaling	[168]
Total secondary ginsenosides	Heart failure	Hypoxia	H9c2	7.5 μg/mL	6 h	Increases ATP content and CK activity and inhibits apoptosis	Upregulates PGC-1α, estrogen-related receptor-α, Nrf-1, Nrf-2, PPARα, and mitochondrial transcription factor A (TFAM), promoting mitochondrial biogenesis	[169]
Rb1	Heart failure	ISO	SD rats	20, 40, 80 mg/kg, i.g.	6 weeks	Improves cardiac function, inhibits cardiac hypertrophy and fibrosis, and increases ATP generation	Promotes the activation of PPARα pathway via inhibiting FADD	[170]
Ginseng	Chronic heart failure	LAD ligation	C57BL/6J mice	1.3, 2.6 g/kg	28 days	Improves heart function, reduces heart damage	Inhibits autophagy via activation of the PI3K/AKT/mTOR pathway	[173]
Rg1	Heart failure	LAD ligation, H2O2	C57BL/6J mice, H9c2	20 mg/kg; (route not specified) 40 μM	28 days; 28 h	Ameliorates cardiac remodeling, reduces cardiac fibrosis, and improves cardiac function	enhances SIRT1/PINK1/Parkin-mediated mitophagy	[174]
Yang-xin-xue keli	Heart failure	DOX	SD rats, H9c2	1.25, 2.5, 5 g/kg, i.g.; 10% YXXKL-medicated serum	4 weeks; 24–48 h	Improves cardiac function and attenuates myocardial injury and fibrosis	Inhibits autophagy/mitophagy by scavenging ROS	[175]
Ginsenoside precursor molecule 20S-O-Glc-DM	Heart failure	ISO	C57B/L6 mice; H9c2	0.3, 1, 3 mg/kg, i.g.; 2 μM	3 weeks; 24 h	Improves LVDD and ameliorates myocardial inflammation and fibrosis	Regulates PGC-1α activity, downregulates PINK1 and Parkin, and reduces excessive autophagy via the AMPK–mTOR–ULK1 pathway	[177]
Shengmai yin	Chronic heart failure	LAD ligation	SD rats	0.906 g/mL × 2 mL, (route not specified)	4 weeks	Restores cardiac function, reduces serum biochemical indicators, and alleviates cardiac histological damage	Regulates linoleic acid metabolism; downregulates arachidonic acid 15 lipoxygenase and cytochrome P450 1A2	[207]
Shenfu formula	Heart failure	LAD ligation	SD rats	2.67 g/kg, oral administration	30 days	Improves cardiac function, increases LV ejection fraction, and reduces serum BNP levels	Suppresses cardiomyocyte apoptosis by regulating Fas/Fas-L, Bcl-2/Bax, caspase-3, and apoptosis-related microRNAs	[179]
Baoyuan decoction	Heart failure	LAD ligation, Ang II	SD rats, H9C2	0.64, 1.28, 2.57 g/kg, oral administration; 400, 600, 800 µg/mL	4 weeks; 48 h	Improves cardiac function and inhibits cardiomyocyte apoptosis	Regulates the AT1–CARP signaling pathway; downregulates AT1 and CARP, upregulates Bcl-2, and downregulates p53, Bax, and cleaved caspase-3	[180]
Fuzheng Yangxin	Heart failure	LAD ligation	SD rats	4.2 g/kg, i.g.	42 days	Improves cardiac function and inhibits cardiomyocyte apoptosis	Promotes STAT3 expression and phosphorylation; potential anti-apoptotic effects	[181]
Xin-Fu-Kang	Chronic heart failure	TAC; phenylephrine	C57BL/6 J mice; H9c2	2.08, 4.16, 8.32 g/kg, i.g.; 8% XFK-medicated serum	8 weeks; Not reported	Improves cardiac function, enhances mitochondrial function, mitigates oxidative stress, and decreases apoptosis	Regulates nuclear receptor subfamily 4 group A member 1	[182]
Shenge formula	Heart failure	Abdominal aortic constriction (AAC)	Male Wistar rats	1.89 g/kg, i.g.	8 or 24 weeks	Improves cardiac function and attenuates myocardial hypertrophy	Modulates the Akt/HIF-1α/p53 pathway, promoting HIF-1α and inhibiting p53 nuclear transport	[184]
Sheng-Mai-San	Heart failure	LAD ligation, OGD	Male ICR mice; H9c2	45.5, 182, 728 mg/kg, orally administered; 25, 100, and 400 µg/mL	3 weeks; 12 h	Improves cardiac function, attenuates myocardial injury, and decreases cardiomyocyte apoptosis	Regulates Ca2+ homeostasis and suppresses mitochondrial-mediated apoptosis via Ca2+/calcineurin A-mediated Drp1 signaling	[185]
Jin-Xin-Kang	Heart failure	TAC, Ang II	C57/BL male mice, H9C2	4.38, 13.14 g/kg, i.g. JXK-L, JXK-H (exact concentrations not specified)	8 weeks; 24 h	Improves cardiac function, reverses ventricular remodeling, and alleviates mitochondrial dysfunction	Inhibits the calcineurin/Drp1 pathway	[186]
Rg5	Hypertensive heart failure	Ang II	H9c2, C57BL/6J mice	5, 10 µM 50 mg/kg, i.g.	1 h + 8–24 h; 2 weeks	Inhibits cardiac inflammation, myocardial fibrosis, and hypertrophy, and prevents cardiac dysfunction	Blocks Ang II-induced JNK/AP-1 signaling and reduces JNK-mediated inflammatory responses	[189]
20(S)-ginsenoside Rh2	Hypertensive heart failure	Ang II	C57BL/6J mice; H9c2	20, 50 mg/kg; i.g. 5, 10 µM	2 weeks; 24 h	Suppresses myocardial fibrosis, hypertrophy, and inflammation	Inhibits JNK/AP-1 signaling and reduces JNK-mediated inflammatory responses	[190]
Xin-Li formula	Heart failure	LAD ligation	C57BL/6J mice	10, 20 g/kg, i.g.	4 weeks	Improves LV function and reduces LV fibrosis and infarct size	Increases Foxp3+ Tregs and inhibits mTOR phosphorylation and NLRP3 inflammasome activation	[191]
Shenfu injection	Heart failure	ISO	SD rats	3, 6, 12 mL/kg, i.g.	15 days	Improves cardiac function and modulates the pro-/anti-inflammatory imbalance	Modulates gut microbiota and microbial metabolism, regulates the TMAO–inflammation axis, and increases Bacteroidota abundance	[192]
Huoxin pill	Heart failure	Verapamil	Zebrafish	5, 10, 20 μg/mL	4 h	Improves cardiac function and reduces cardiac inflammation and apoptosis	Inhibits ROS and H2O2 production, increases CAT activity, and suppresses NF-κB-associated inflammation and apoptosis	[194]
Qiliqiangxin	Heart failure	TAC	SD rats	100 mg/kg/day, i.g.	13 weeks	Preserves cardiac function and ameliorates ventricular remodeling	Modulates gut microbiota and inhibits NLRP3 inflammasome-associated inflammation	[197]
Shenfu injection	Heart failure	DOX	SD rats	6 mL/kg, i.p.	15 days	Improves myocardial energy metabolism and cardiac function	Regulates gut microbiota, particularly SCFA-producing Akkermansia and Blautia, and improves intestinal health	[198]
Dengzhanshengmai capsule	Heart failure	LAD ligation	SD rats	226.8 mg/kg, i.g.	32 days	Reduces systemic inflammation, improves intestinal barrier function, and enhances cardiac function	Modulates gut microbiota and reduces phenylacetylglutamine (PAGln) levels by regulating PAGln synthesis-related enzymes	[200]
Re	Myocardial fibrosis and heart failure	ISO	Male Wistar rats	5, 20 mg/kg, oral administration	4 weeks	Improves cardiac function and attenuates myocardial fibrosis	Regulates the TGF-β1/Smad3 pathway and reduces collagen I expression	[205]
Qiliqiangxin	Heart failure	Dox	Male Wistar rats	1.0 g/kg, i.g.	4 weeks	Improves cardiac function and attenuates cardiac remodelling	Promotes TGF-β3/Smad7 signaling and inhibits TGF-β1/Smad3 signaling	[206]

Across different stages of the cardiovascular continuum, ginseng-related interventions appear to act through several interconnected mechanisms rather than isolated signaling pathways. Metabolic regulation and mitochondrial homeostasis are closely associated with oxidative stress, inflammation, and regulated cell death, whereas calcium handling and autophagy contribute to myocardial function and remodeling. To facilitate a cross-sectional comparison of the mechanistic evidence discussed throughout this review, Table 3 summarizes key experimental findings and evidence levels for selected molecular targets and pathways.

Table 3. Key molecular mechanisms and supporting evidence for the cardiovascular protective effects of ginsenosides.

Target/ Mechanism	Intervention	Key Mechanistic Evidence	Evidence Level	Ref.
PPARγ/FAK	Rg3	GW9662 inhibition; endothelial protection; reduced atherosclerotic lesions	Pathway-level evidence	[74]
Nrf2/GPX4-associated ferroptosis regulation	Rg3	Nrf2 activation; GPX4 expression; siRNA validation	Pathway-level evidence	[114]
PPARγ/HMGCS2	Rd	SPR; GW9662 inhibition; cardiac-specific Hmgcs2 knockdown/overexpression	Direct target and pathway-level evidence	[134]
P300/DLD/PDH	Rg3	Reduced DLD 2-hydroxyisobutyrylation; restored PDH activity	Pathway-level evidence with biochemical validation	[153]
SIRT1/PINK1/Parkin-mediated mitophagy	Rg1	EX527 inhibition; Parkin siRNA	Pathway-level evidence with functional validation	[174]
FADD/PPARα	Rb1	FADD interaction; enhanced PPARα transcriptional activity and fatty acid oxidation	Direct target and pathway-level evidence	[170]
SERCA2a-associated Ca2+ regulation	Rg3	Increased SERCA2a SUMOylation and activity; SUMO1 knockout and SERCA2a SUMOylation-site mutation	Pathway-level evidence with genetic validation	[202]
RyR2-associated Ca2+ handling	Rb1	Reduced RyR2-mediated Ca2+ leakage; improved Ca2+ signaling	Pathway-level evidence	[208]

8. Translational Considerations

8.1. Effective Concentrations and Pharmacokinetic/Pharmacodynamic Considerations

The pharmacological effects of ginseng-derived constituents depend on their effective concentrations, administration routes, and systemic exposure. As summarized in Table 1 and Table 2, ginsenosides have demonstrated beneficial effects across various cellular and animal models at different experimental concentrations and doses. Despite their diverse pharmacological activities, many ginsenosides exhibit low oral bioavailability, which may be associated with their physicochemical properties, limited intestinal permeability, and extensive gastrointestinal metabolism [209].

Representative pharmacokinetic parameters of selected ginsenosides from preclinical and human studies are summarized in Table 4. For example, the oral bioavailability of purified ginsenoside Re was only 0.19–0.28% in mice, while ginsenoside Re administered as ginseng berry extract exhibited a higher bioavailability of 0.33–0.75% at equivalent Re doses [210]. This Study suggested that ginseng berry extract might be a good form for ginsenoside Re intake. These findings suggest that formulation composition may influence the absorption and systemic exposure of individual ginsenosides. Human pharmacokinetic studies have also demonstrated measurable systemic exposure following administration of isolated ginsenosides or ginseng preparations. Nevertheless, marked discrepancies across studies in experimental species, formulations and administration routes preclude direct cross-study comparisons.

Table 4. Representative pharmacokinetic parameters of selected ginsenosides in preclinical and human studies.

Compound/Preparation	Species/Subjects	Route	Dose	Key Pharmacokinetic Parameter(s)	Refs.
Preclinical studies
Re (purified)	Mouse	Oral	10, 50 mg/kg	F: 0.19–0.28%	[210]
Re (ginseng berry extract)	Mouse	Oral	90.5, 452.5 mg/kg	F: 0.33–0.75%	[210]
20(S)-Rh1	Rat	Oral	50 mg/kg	F: 1.01%	[211]
Rh2	Rat	Oral	1, 3, 9 mg/kg	F: 4.7%, 4.0%, 6.4%	[212]
Rh2	Dog	Oral	1 mg/kg	F: approximately 16%	[212]
Compound K	Rat	Oral	5–20 mg/kg	F: 1.8–35.0%	[213]
Human studies
20(S)-Rg3	Healthy volunteers	Intramuscular	10, 30, 60 mg	Cmax: 135.4, 162.1, 399.8 ng/mL	[214]
Compound K	Healthy volunteers	Oral	25–800 mg	Cmax: 175.1 ± 35.1–1183.2 ± 445.1 ng/mL; t½: 13.5 ± 0.6–25.7 ± 3.0 h	[215]
Compound K (after oral ginseng administration)	Healthy volunteers	Oral	12 g ginseng powder	Cmax: 27.89 ± 24.46 ng/mL; Tmax: 10.76 ± 2.07 h	[216]

Abbreviations: F, absolute oral bioavailability; C_max, maximum plasma concentration; T_max, time to maximum plasma concentration; t½, elimination half-life.

Importantly, although pharmacokinetic and pharmacological studies of ginsenosides have been conducted, quantitative pharmacokinetic–pharmacodynamic relationships linking circulating ginsenoside concentrations to cardiometabolic and cardiovascular outcomes remain insufficiently characterized. Effective concentrations observed in vitro cannot be directly extrapolated to clinically achievable plasma concentrations. The effective concentrations of ginsenosides used in vitro may substantially exceed the plasma concentrations achieved following oral administration of ginseng preparations, limiting the direct translation of preclinical findings to clinical settings.

8.2. Cardiovascular Safety, Population Differences, and Structure–Activity Relationships

Although ginseng is a natural medicine and has shown promising therapeutic effects in preclinical experiments, its potential toxicological effects in the cardiovascular system cannot be ignored. By reviewing the current research, no serious adverse reactions of ginseng on the human body have been found, most of them are mild and temporary symptoms such as dyspepsia, hot flushes and insomnia [217]. However, the limited nature of clinical studies makes this conclusion rather limited. It is hoped that more evidence will be available to demonstrate that ginseng has no obvious toxicological effects on the human body. Meanwhile, the clinical effects of ginseng may vary across populations because of differences in dietary habits, consumption patterns, preparation types, and individual metabolic characteristics. Studies have demonstrated substantial interindividual variability in intestinal microbiota-mediated ginsenoside metabolism [218]. However, comparative clinical evidence across different ethnic and geographic populations remains limited. Further studies involving diverse populations are therefore needed to evaluate the generalizability of existing findings.

The biological activities of ginsenosides and other active components are significantly influenced by their chemical structures. Although this has been discussed in current research [219,220], there is still a lack of quantitative structure–activity relationships (QSAR) specifically addressing the effects on cardiac metabolism and cardiovascular systems. Future QSAR studies may help clarify the relationships between the molecular structures of ginsenosides and their cardiovascular protective activities.

9. Conclusions and Future Perspectives

The cardiovascular continuum provides a useful framework for integrating the diverse cardiovascular actions of Panax ginseng across different stages of disease, ranging from cardiometabolic risk factors and atherosclerosis to myocardial ischemic injury, pathological cardiac remodeling, and heart failure. Across these stages, several recurring mechanisms emerge, including regulation of metabolic and mitochondrial homeostasis, oxidative stress and inflammation, autophagy and mitophagy, regulated cell death, calcium handling, vascular and fibrotic remodeling, and gut microbiota–host interactions. Rather than acting through a single pathway, ginseng-related interventions appear to influence interconnected regulatory networks whose relative importance varies according to disease stage and pathological context.

Nevertheless, the strength of mechanistic evidence remains uneven. A substantial proportion of current studies infer mechanisms from changes in signaling proteins, gene expression, or downstream phenotypes, whereas direct molecular target evidence and rigorous causal validation are comparatively limited. Several studies have begun to provide more target-oriented mechanistic insights, including regulation of P300/DLD/PDH-associated metabolic remodeling, RyR2-dependent Ca²⁺ handling, FADD/PPARα signaling, and SERCA2a SUMOylation. Future studies should move beyond pathway association toward direct target engagement and causal validation using complementary approaches such as genetic perturbation, pharmacological intervention, and rescue experiments.

Another important consideration is the heterogeneity of ginseng-related interventions. Whole ginseng, ginseng extracts, isolated ginsenosides, polysaccharides, ginsenoside derivatives, and multi-herbal formulations should not be regarded as equivalent levels of evidence. In particular, the biological effects of ginseng-containing formulas cannot be attributed specifically to ginseng without component-resolved validation. In addition, the relatively low bioavailability of several ginsenosides remains an important barrier to translation. Further studies are therefore needed to clarify the active constituents responsible for cardiovascular effects, improve their bioavailability, and establish more robust relationships between administered dose, biological exposure, and pharmacological response.

Clinical translation also remains limited because most available evidence is derived from preclinical models, and the relevance of these models to the heterogeneity and complexity of human cardiovascular disease requires further validation. Well-designed clinical studies using clearly characterized ginseng preparations, appropriate patient populations, and clinically meaningful cardiovascular endpoints could be essential to determine whether the mechanistic benefits observed experimentally can be reproduced in humans. Overall, future research should shift from broad claims of “multi-target” activity toward experimentally validated target networks and better-defined ginseng interventions. Such an approach may provide a stronger mechanistic and translational basis for evaluating the role of Panax ginseng in cardiovascular disease.