Challenges and opportunities for ginseng-based medicines in treating cardiac fibrosis from mechanistic insights to clinical translation

Abstract

Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition and progressive myocardial remodeling, is a common pathological outcome of various cardiovascular diseases and lacks effective targeted anti-fibrotic therapies. Panax ginseng and its related preparations, including major ginsenosides (e.g., Rb₁, Rg₁, and Rg₃), standardized extracts, and compound formulas, have garnered growing interest owing to their multi-component, multi-target pharmacological activities and integrative regulatory effects. This review systematically summarizes recent advances in the basic and clinical research of ginseng-based medicines in the prevention and treatment of cardiac fibrosis. Preclinical evidence demonstrates that ginseng and its active constituents attenuate key pathological processes, including oxidative stress, inflammatory responses, apoptosis, and autophagy dysregulation, primarily through modulation of signaling pathways such as TGF-β/Smad, NF-κB, and PI3K/Akt. These regulatory effects collectively contribute to the inhibition of fibroblast activation, reduction of collagen deposition, and improvement of myocardial structure and function. Emerging clinical studies further suggested potential benefits in improving cardiac function and modulating fibrosis-related biomarkers in patients with hypertension, coronary heart disease, and heart failure (HF). Despite these promising findings, several challenges hinder clinical translation, including low oral bioavailability, the mechanistic complexity of compound formulas, and insufficient high-quality clinical evidence. Future investigations should integrate novel drug delivery strategies, systems pharmacology approaches to elucidate holistic mechanisms, and well-designed randomized controlled trials to facilitate the development of ginseng-based medicines as potential therapeutic agents for cardiac fibrosis.

1. Introduction

Cardiac fibrosis is a pivotal pathological process in the onset and progression of multiple cardiovascular diseases and a fundamental driver of progressive deterioration in myocardial structure and function (Chen et al., 2023, Frangogiannis, 2019). It is characterized by activation of cardiac fibroblasts (CFs) and their transdifferentiation into myofibroblasts, which promotes excessive deposition of extracellular matrix (ECM) components such as type I and type III collagen. The resulting increase in myocardial stiffness reduces ventricular compliance, impairs systolic and diastolic function, and ultimately elevates the risk of adverse outcomes including heart failure (HF) and arrhythmia (Chen et al., 2022, Li et al., 2014, McCracken et al., 2024, Travers et al., 2016, Yu, 2023). In this review, cardiac fibrosis encompasses both interstitial fibrosis and replacement fibrosis; when the original studies explicitly distinguish these entities, we retain the authors’ terminology.

Although guideline-directed therapies such as ACE inhibitors/angiotensin receptor blockers (ACEIs/ARBs), β-blockers, and mineralocorticoid receptor antagonists can delay ventricular remodeling by unloading the heart and modulating neurohormonal activation, their direct inhibitory effects on fibrotic progression are limited, and they have no clearly established ability to reverse established fibrotic tissue (Parichatikanond et al., 2020, Ravassa et al., 2023). Therefore, identifying more direct anti-fibrotic interventions targeting fibroblast activation, ECM metabolic imbalance, and the coupling between inflammation and oxidative stress, and evaluating their additive or synergistic effects in conjunction with standard therapy, have become urgent translational needs (Czubryt and Hale, 2021, Sehgal et al., 2022).

Ginseng and ginseng-based preparations have long been used in East Asia as adjunctive therapies for cardiovascular diseases, with accumulated clinical experience. Modern pharmacological studies indicate that their major active constituents include multiple ginsenosides, which may act in concert with polysaccharides and other components, thereby producing multi-component, multi-target pharmacological effects (Guan and Qi, 2023, Jovanovski et al., 2014, Lee et al., 2023, Wang et al., 2009, Xu et al., 2019, Xu et al., 2024, Ling et al., 2024). A large body of preclinical work suggested that ginsenoside monomers, extracts, and compound formulations can intervene in fibrotic remodeling through antioxidant and anti-inflammatory actions, inhibition of fibroblast activation, and modulation of cell death and autophagy (Cui et al., 2024, Li et al., 2020, Ren et al., 2021, Xu et al., 2024, Lu et al., 2023). However, most existing clinical studies of ginseng-related preparations evaluate symptom relief, functional improvement, or risk-factor control rather than direct indices of fibrosis, such as imaging or biomarkers. In addition, active constituents responsible for efficacy are often unclear, dose selection is not systematically linked to efficacy verification, and key mechanistic nodes remain insufficiently defined. Consequently, whether the reported benefits truly reflect verifiable anti-cardiac fibrotic effects requires more rigorous scientific evidence.

Accordingly, this review uses fibrosis-related evaluation metrics as a unifying thread to integrate preclinical evidence, map mechanistic actions onto pathological steps, and critically appraise the endpoints used in clinical studies. On this basis, we propose translational research recommendations for combination use alongside standard therapy. Specifically, in preclinical studies, we emphasize standardized and optimized reporting of direct fibrosis readouts, including Masson/Sirius Red staining area, markers such as collagen I/III and hydroxyproline (HYP), and α-SMA expression. In clinical studies, we stratify evidence according to whether cardiac magnetic resonance (CMR) T1 mapping/extracellular volume (ECV), late gadolinium enhancement (LGE), or fibrosis-related biomarkers are used. We also clarify that ginseng-based preparations should be positioned primarily as adjuncts to guideline-directed therapy rather than replacements, and we provide actionable suggestions on standardized manufacturing, dose exploration, and clinical validation to support a clearer path for translation.

2. Core molecular mechanisms of cardiac fibrosis

This section synthesizes the key pathological steps in the initiation and progression of cardiac fibrosis, with the aim of aligning potential action nodes of ginseng-related agents (ginsenoside monomers, extracts, and compound formulations) with fibrosis assessment indicators that have translational value. For readability, Fig. 1 summarizes and schematically illustrates the major signaling pathways discussed.

Fig. 1.

Cellular signaling pathway network involved in the progression of cardiac fibrosis (Created with BioRender.com).

2.1. Fibroblast activation and myofibroblast differentiation: TGF-β/Smad axis

During cardiac fibrosis, activation of CFs and their transdifferentiation into myofibroblasts are considered key drivers of excessive ECM accumulation. The transforming growth factor-β (TGF-β) signaling pathway plays a central role in this process by promoting Smad2/3 phosphorylation and nuclear translocation, upregulating α-SMA expression, and enhancing transcription of collagen genes, thereby accelerating ECM deposition and tissue stiffening. Available evidence suggested that ginsenosides can modulate this pathway. For example, Rg₃ has been reported to inhibit collagen production by targeting TGFBR1/Smads (Ni et al., 2017, Xu et al., 2023b), and Re and Rd are also closely linked to regulation of TGF-β1/Smad signaling (Wang et al., 2019, Yu et al., 2020, Zhang et al., 2019).

2.2. Imbalanced ECM deposition and remodeling: Quantifying collagen synthesis and degradation

A defining pathological feature of fibrosis is the dynamic imbalance between ECM synthesis and degradation. Even if fibroblast activation is attenuated, persistent enhancement of collagen synthesis or impaired degradation can still lead to progressive collagen accumulation and structural stiffening. In preclinical studies, anti-fibrotic effects of ginsenosides and compound formulations are often reflected by reduced collagen deposition, such as decreased collagen I/III expression, lower HYP content, and smaller fibrotic areas on Masson or Sirius Red staining (Section 3 in detail).

From a translational perspective, targeting the ECM axis has the advantage of intuitive and quantifiable readouts; however, many studies still lack systematic assessment of remodeling processes such as collagen crosslinking and the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).

Common fibrosis readouts include Masson or Sirius Red fibrotic area, collagen volume fraction, HYP, collagen I/III, fibronectin, connective tissue growth factor (CTGF), and, when applicable, MMP/TIMP profiles.

2.3. Inflammation and immune microenvironment: NF-κB and inflammasomes in fibrotic progression

Inflammation not only triggers fibrosis but can also sustain its progression once fibrosis has formed. NF-κB-mediated transcription of proinflammatory genes, macrophage infiltration and phenotypic shifts, and activation of inflammasomes such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) can all promote fibroblast activation and ECM deposition through cytokines including interleukin-1β (IL-1β). In ginseng-related studies, Rb₁ and Rg₃ have been reported to suppress inflammatory amplification via the Sirtuin 1 (SIRT1)/NF-κB axis and inhibit NLRP3 inflammasome activation (Jiang et al., 2021, Ren et al., 2021). Ginseng-containing injections have also been reported to attenuate myocardial inflammation and apoptosis in lipopolysaccharide-induced myocardial injury models (Chen et al., 2020), and Shenmai Injection (SMI) has been suggested to modulate AIM2 inflammasome activity (Xu et al., 2025).

Because inflammatory processes are tightly intertwined with metabolic stress and oxidative stress, mechanistic interpretations should distinguish whether anti-fibrotic effects arise indirectly from upstream anti-inflammatory actions that secondarily blunt remodeling or from direct blockade of fibrotic signaling and ECM production.

Common readouts include cytokines such as IL-1β, IL-6, and TNF-α; NF-κB activation (p65 nuclear translocation or phosphorylation); NLRP3/AIM2 and caspase-1; and inflammatory cell infiltration and macrophage polarization (M1/M2 markers).

2.4. Oxidative stress and mitochondrial dysfunction: Nrf2/Keap1 antioxidant pathway

Oxidative stress is a common pathogenic factor underlying diverse forms of myocardial injury and fibrotic remodeling. Excess reactive oxygen species (ROS) not only directly damage cardiomyocytes and mitochondria but also promote fibroblast activation through crosstalk with inflammation. The Nrf2/Keap1 antioxidant signaling pathway is a pivotal regulator of cellular antioxidant defense, and multiple studies indicate that ginsenosides can enhance this pathway to reduce oxidative burden. For example, Rb₁ has been reported to suppress mitochondrial ROS generation through the Keap1/Nrf2 pathway, thereby attenuating remodeling associated with fibrosis (Jiang et al., 2021, Yao et al., 2022). In addition, F₂ and red ginseng polysaccharides have been linked to Nrf2/HO-1-mediated antioxidant actions (Cui et al., 2024, Lian et al., 2022).

Notably, lowering ROS alone does not necessarily equate to reversing fibrosis; in many contexts it mainly acts by dampening inflammatory amplification. Therefore, oxidative stress should be viewed as an important upstream driver within the pathological cascade rather than a fibrosis-specific endpoint.

Common readouts include ROS or superoxide levels, malondialdehyde (MDA), antioxidant indices such as superoxide dismutase and glutathione, Nrf2 nuclear translocation and HO-1 expression, and mitochondrial functional measures such as membrane potential and ATP production.

2.5. Dysregulated cell death and autophagy: Interplay among apoptosis, autophagy, and ferroptosis

Cardiomyocyte death and disrupted autophagic homeostasis can promote fibrosis indirectly by releasing damage-associated molecular patterns, reshaping the immune microenvironment, and altering mechanical stress. In parallel, autophagy within fibroblasts can influence their activation and ECM secretion. In ginseng-related studies, Rb₁ was reported to attenuate cardiac remodeling in a doxorubicin cardiotoxicity model by inhibiting autophagy and ferroptosis (Zhai et al., 2024); Rg₁ enhances mitophagy via the SIRT1/PINK1/Parkin pathway to maintain mitochondrial homeostasis (Guan et al., 2023, Qiao et al., 2018, Yang et al., 2020); Shenfu Injection (SFI) was also shown to regulate autophagy through the PI3K/Akt/mTOR pathway, thereby improving ischemia-reperfusion injury (Tsang et al., 2018). Apoptosis can proceed via intrinsic mitochondrial pathways and extrinsic death-receptor signaling (Chang et al., 2016). More broadly, interventions that concurrently regulate autophagy and oxidative stress can reduce myocardial ischemia-reperfusion injury and subsequent remodeling (Yuan, Yang, Lan, Yang, & Tang, 2024).

Common readouts include TUNEL staining, cleaved Caspase-3, and Bax/Bcl-2 as apoptosis markers; autophagic flux indices such as LC3-II/I and p62; mitophagy markers such as PINK1 and Parkin; and ferroptosis-related factors, such as glutathione peroxidase 4 and lipid ROS, together with corresponding changes in collagen deposition.

2.6. Integrated network synthesis of ginsenosides

Recent studies suggested that major ginsenosides, such as Rb₁, Rg₁, and Rg₃, do not act in isolation but form a functional network that collectively regulates cardiac fibrosis through interconnected signaling pathways (Gao et al., 2024b). Rb₁ primarily enhances antioxidant defenses (via the Keap1/Nrf2 pathway) and suppresses TGF-β/Smad-driven fibroblast activation, consequently reducing extracellular matrix deposition. Rg₁ mainly modulates immune-metabolic axes, such as macrophage polarization and SIRT1-autophagy, indirectly constraining pro-fibrotic inflammation (Guan et al., 2023, Qin et al., 2019). Rg₃ exerts stronger inhibitory effects on inflammatory signaling (like NF-κB/NLRP3) while directly antagonizing TGF-β receptor–Smad signaling (Wang et al., 2022). The crosstalk among these pathways suggested potential synergistic effects, where antioxidant actions mitigate inflammatory amplification, jointly diminishing TGF-β-driven fibrosis (Yang et al., 2025). Furthermore, while individual ginsenosides target specific molecules, their anti-fibrotic efficacy often arises from this synergistic network. For instance, Rb₁ and Rg₃ concurrently modulate the TGF-β/Smad pathway at different levels: Rb₁ suppresses Smad2/3 phosphorylation, whereas Rg₃ directly inhibits the receptor TGFBR1. Simultaneously, Rg₁ complements this effect by addressing the inflammatory microenvironment through M2 macrophage polarization. This multi-layered intervention indicates that the clinical benefits of ginseng result not from a single factor, but from a coordinated regulation of the interplay between oxidative stress, inflammation, and the core fibrotic cascade.

3. Preclinical evidence for ginseng-based medicines against cardiac fibrosis: Cell experiments and animal models

3.1. Anti-cardiac fibrosis effects of major active monomers

Ginsenosides are the primary active components responsible for the pharmacological effects of ginseng, and their role in inhibiting cardiac fibrosis is gaining increasing attention. Numerous studies have shown that various individual ginsenosides exhibit significant potential in intervening in the process of cardiac fibrosis (Guan and Qi, 2023, Wu et al., 2024). This section systematically reviews the latest research progress on representative ginsenoside monomers-including Rb₁, Rg₁, Rg₂, Rg₃, Re, Rh₂, Rd, Rh₄, F₂, C-K, Ro, and AD₂-in the context of anti-cardiac fibrosis. For each monomeric study, we follow a consistent narrative sequence: we first report fibrosis-related phenotypes and quantitative readouts (e.g., Masson or Sirius Red fibrotic area, collagen content, collagen I/III, and α-SMA), then describe commonly used models, administration routes, and dose ranges, and finally summarize the likely pathological steps and molecular targets involved.

3.1.1. Anti-fibrotic effects of ginsenoside Rb₁ and its mechanisms

Across multiple models of myocardial injury and remodeling, Rb₁ reduces the degree of fibrosis as evidenced by decreased collagen deposition and smaller fibrotic areas, accompanied by improved cardiac function (Jiang et al., 2021, Yao et al., 2022, Zheng et al., 2017). In addition, in doxorubicin-induced cardiotoxicity and under metabolic stress conditions such as hyperglycemia and hyperlipidemia, Rb₁ similarly attenuates remodeling-associated fibrotic features (Zhai et al., 2024, Zhang et al., 2023).

Mechanistically, Rb₁ has been reported to enhance antioxidant responses through Keap1/Nrf2 and reduce mitochondrial ROS, thereby suppressing fibroblast activation (Jiang et al., 2021, Yao et al., 2022); It can also inhibit NLRP3 inflammasome activation and oxidative stress amplification via the SIRT1/NF-κB axis (Ren et al., 2021). In HF-related remodeling, Rb₁ may further influence pathways including TGF-β1/Smad, ERK, and Akt, improving cardiac hypertrophy and fibrosis (Zheng et al., 2017). Recent evidence also suggested that Rb₁ suppresses M1 macrophage-induced IGFBP2-mediated endothelial-to-mesenchymal transition (EndMT), attenuating fibrosis through immune-vascular interactions (Jiang et al., 2025).

In conclusion, ginsenoside Rb₁ demonstrates significant potential for cardioprotection and anti-fibrosis through multi-target and multi-pathway mechanisms. However, because disease models and dosing regimens vary substantially across studies, future work should further standardize fibrosis endpoints and dosing rationales to improve comparability and translational relevance.

3.1.2. Anti-fibrotic effects of ginsenoside Rg₁ and its mechanisms

Ginsenoside Rg₁ has shown anti-remodeling and anti-fibrotic potential in several cardiovascular injury models. In myocardial ischemia/reperfusion injury, Rg₁ reduced inflammation and attenuated fibrotic remodeling, in part by inhibiting proinflammatory macrophage polarization (Xu et al., 2024). In models of mechanical stress or pressure overload, Rg₁ improved cardiac structure and function and decreased fibrosis-related markers, with evidence implicating calcium-sensing receptor (CaSR)-related signaling (Lu et al., 2021). In HF models, Rg₁ mitigated adverse remodeling by enhancing mitophagy and mitochondrial homeostasis (Guan, Xin, Ding, Zhang, & Han, 2023).

Mechanistically, Rg₁ appears to act at the interface of inflammation, mitochondrial quality control, and fibroblast activation. Reported mechanisms include regulation of macrophage polarization and inflammatory cytokine production, activation of SIRT1-dependent mitophagy via the PINK1/Parkin pathway, and downstream attenuation of pro-fibrotic signaling and ECM accumulation (Xu et al., 2024). Emerging data also suggested that Rg₁ may exert anti-fibrotic effects indirectly by modulating paracrine immunoregulatory pathways, such as promoting M2 macrophage polarization via Rg₁-primed mesenchymal stem cell-derived exosomal signals in diabetic cardiomyopathy (DCM) (Zhen, Bai, Liu, Men, & Yu, 2024).

Collectively, available evidence indicates that Rg₁ confers cardioprotection by jointly modulating inflammation, mitochondrial function, and fibrotic remodeling, providing a pharmacological basis for further translational development.

3.1.3. Anti-fibrotic effects of ginsenoside Rg₃ and its mechanisms

Rg₃ has demonstrated a relatively clear anti-fibrotic effect across multiple models of myocardial remodeling: it inhibits cardiac fibroblast proliferation, reduces collagen synthesis and deposition, and improves cardiac function (Xu et al., 2023b). In the context of angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, Rg₃ also attenuates remodeling responses associated with inflammation and oxidative stress (Ren et al., 2021). In HF models, Rg₃ improves adverse remodeling by alleviating fibrosis (Lai et al., 2022).

Mechanistically, Rg₃ has been reported to suppress NLRP3 inflammasome activation via the SIRT1/NF-κB pathway and to reduce the amplification of oxidative stress (Ren et al., 2021); In HF models, Rg₃ can also upregulate aminoacylase 1 and inhibit TGF-β1/Smad3 signaling (Lai et al., 2022). In addition, Rg₃ may directly act on the TGF-β1/Smad axis to inhibit fibroblast-driven collagen production (Xu et al., 2023a), and some studies suggested that it may influence the transcriptional activity of the Wnt/β-catenin pathway (Deb, 2014, Nag et al., 2012, Zhao et al., 2019).

These findings collectively indicated that Rg₃ plays a significant protective role in the process of cardiac remodeling through its anti-inflammatory, antioxidant, and anti-fibrotic mechanisms.

3.1.4. Anti-fibrotic effects of ginsenosides Rg₂ and Rh₂ and their mechanisms

In a model of acute myocardial infarction (AMI), ginsenoside Rg₂ has shown significant cardioprotective effects. Research indicates that Rg₂ can activate the Akt signaling pathway, improve cardiac systolic and diastolic function, and significantly reduce collagen deposition in the infarcted area (Li, Xiang, & Wang, 2020). Another study further revealed that Rg₂ can effectively inhibit cardiac fibrosis by regulating the TGF-β1/Smad signaling pathway, thereby improving cardiac function in rats with myocardial ischemia (Wang et al., 2021).

Ginsenoside Rh₂ also exerts protective effects in various cardiac injury models. In a diabetic rat model with cardiac fibrosis, Rh₂ improved cardiac function and reduced fibrosis by activating PPARδ and inhibiting the STAT3 signaling pathway, which led to the downregulation of CTGF and fibronectin expression (Lo et al., 2017). In a myocardial infarction (MI) model, Rh₂ was able to restore mitochondrial bioenergetics and alleviate cardiac injury by activating ERK-dependent pathways (Duan et al., 2025). Furthermore, in a doxorubicin-induced cardiotoxicity model, Rh₂ significantly attenuated pathological cardiac remodeling by inhibiting cardiomyocyte apoptosis and inflammation (Hou, Yun, Cui, & Kim, 2022).

These studies collectively demonstrate that Rg₂ and Rh₂ have significant potential in inhibiting cardiac fibrosis and improving cardiac function by modulating multiple signaling pathways, including Akt, TGF-β1/Smad, PPARδ/STAT3, and ERK.

3.1.5. Roles of ginsenosides F₂, Re, Rd, Rh₄, C-K, Ro, and AD₂

Various individual ginsenosides have demonstrated multi-target effects in the regulation of cardiac fibrosis. Ginsenoside F₂ improves post-MI cardiac structure and function by activating the Nrf2/HO-1 and PI3K/Akt signaling pathways, which mitigates cardiomyocyte apoptosis, oxidative stress, and mitochondrial dysfunction (Cui et al., 2024). Ginsenoside Re primarily modulates the TGF-β1/Smad3 pathway to ameliorate isoproterenol (ISO)-induced cardiac fibrosis and HF (Wang, Yu, Xu, Zhao, & Sui, 2019). Additionally, Re can alleviate left ventricular interstitial fibrosis and improve cardiac function after MI by regulating the AMPK/TGF-β1/Smad2/3 and FAK/PI3K p110α/Akt pathways (Yu, Sun, Liu, Wang, & Wang, 2020).

In a pressure overload model, ginsenoside Rd improves cardiac dysfunction and remodeling by inhibiting key proteins such as Akt, calcineurin A, ERK1/2, and TGF-β1 (Zhang, An, Lang, Wang, & Xie, 2019). In a MI model, Rd promotes the conversion of Ly6C (low) to Ly6C (high) monocytes/macrophages via the Akt/mTOR signaling pathway, significantly improving myocardial function, alleviating cardiac fibrosis, and inhibiting post-infarction inflammation and apoptosis in mice (Zhao et al., 2022). Ginsenoside Rh₄ can significantly inhibit Ang II-induced myocardial hypertrophy, inflammation, fibrosis, and oxidative stress, suggesting its therapeutic potential for cardiac hypertrophy and fibrosis (Wang, An, Wang, & Jiang, 2024).

An albumin-nanoparticle formulation of compound K (nabCK) restores lipid homeostasis by inhibiting the mTOR pathway, delays the progression of non-alcoholic fatty liver disease, and shows protective effects against lipotoxicity in cardiac tissue in a high-fat diet-induced model (Yue et al., 2023). Ginsenoside Ro alleviates age-related cardiac fibrosis by promoting the TGFBR3/ALK1/Smad1 signaling pathway and interacting with FBLN7 (Zheng et al., 2025). AD₂ prevents Ang II-induced dysregulation of connexins Cx40 and Cx43 by activating the AMPK signaling pathway (Li et al., 2021, Wu and Zou, 2020). Furthermore, ginsenoside Rg₅ attenuates Ang II-induced cardiac inflammation and remodeling by inhibiting the JNK/AP-1 pathway (Yu et al., 2023), while ginseng fruit saponins combined with metoprolol significantly improves cardiac function and inhibits fibrosis in a mouse model of MI (Liu, Liu, Zhang, Geng, & Ge, 2019).

In summary, the aforementioned ginsenoside monomers have all demonstrated the potential to inhibit cardiac fibrosis in various experimental models. Their mechanisms encompass the regulation of oxidative stress, inflammation, apoptosis, connexin homeostasis, and multiple key signaling pathways, providing crucial theoretical support for the subsequent development of individual ginsenosides as anti-cardiac fibrosis drugs.

3.2. Anti-cardiac fibrosis effects of ginseng extracts

Ginseng extracts are rich in a variety of active components, including ginsenosides, polysaccharides, volatile oils, and flavonoids, and possess multiple pharmacological effects such as antioxidant, anti-inflammatory, anti-apoptotic, and myocardial remodeling regulation (El-Saadony et al., 2025, Xu et al., 2016). Compared to single ginsenoside components, their synergistic effects are more relevant to clinical applications. Additionally, saponins of Panax quinquefolium L. have been reported to enhance angiogenesis and improve post-MI remodeling in diabetic rats (Pan et al., 2024).

In terms of anti-cardiac fibrosis, red ginseng polysaccharides have shown promising therapeutic potential. Studies have indicated that red ginseng polysaccharide (RGP_1-1) can significantly reduce serum levels of cardiac troponin I, aspartate aminotransferase, lactate dehydrogenase, and MDA in mice with myocardial ischemia, and it can inhibit cardiomyocyte apoptosis and cardiac fibrosis (Lian et al., 2022). Further mechanistic studies revealed that RGP_1-1 may activate the Nrf2/HO-1 signaling pathway, enhancing the body's antioxidant capacity and thereby alleviating ISO-induced myocardial ischemic injury (Lian et al., 2022). These results suggested that red ginseng polysaccharides may exert their anti-fibrotic effects by mitigating oxidative stress and inflammation and inhibiting apoptosis. Additionally, Korean red ginseng (KRG) extract has been confirmed to produce significant cardioprotective effects in an ISO-induced MI model by enhancing the antioxidant defense mechanisms of myocardial tissue (Lim, Ko, & Kim, 2013).

3.3. Anti-cardiac fibrosis effects of compound formulas containing ginseng

Ginseng and its related preparations often exert their effects in the treatment of cardiac fibrosis through the synergistic actions of multiple components and targets. Compared to single components, ginseng extracts and their compound formulas demonstrate more comprehensive pharmacological activity and clinical applicability in intervening in the process of cardiac fibrosis (de Moraes et al., 2019, Liu et al., 2020). This section will systematically elaborate on the overall mechanisms and research progress of these formulas in combating cardiac fibrosis.

Experimental studies indicate that a variety of ginseng-containing compound formulas can reduce fibrotic area or collagen deposition and improve structural and functional remodeling in models including ischemic injury, pressure overload, hypertensive heart failure, and radiation- or drug-induced myocardial injury. Representative preparations include SFI, SMI, Qishen Yiqi Dripping Pills (QSYQ), Yixin Fumai Granules (YXFM), Xinyin Tablets (XYT), Huangqi Shengmai Liquid (HQSML), and other ginseng-containing formulas. These preparations appear to modulate cardiac fibrosis synergistically through multiple pathways and pathological steps.

Injectable preparations. SMI and SFI are commonly used traditional Chinese medicine (TCM) injections in clinical practice (Yang et al., 2024). SMI can exert protective effects in a radiation-induced myocardial injury model by inhibiting oxidative stress and structural remodeling. In a salt-sensitive hypertensive heart failure model, SMI inhibits cardiac fibrosis and improves cardiac function by regulating the TGF-β1/Smad signaling pathway (Hu et al., 2023). SFI can alleviate fibrosis caused by myocardial ischemia-reperfusion injury by activating the adenosine A₂a receptor (Guo et al., 2022). SFI can also regulate autophagy via the PI3K/Akt/mTOR pathway and attenuate myocardial inflammation and apoptosis in lipopolysaccharide-induced myocardial injury models (Chen et al., 2020). In addition, SMI can alleviate doxorubicin-induced myocardial injury by suppressing autophagy-apoptosis via miR-30a (Li et al., 2023), while SFI can protect against sepsis-induced myocardial injury by inhibiting mitochondrial apoptosis (Xu et al., 2020).

Oral preparations also exhibit multi-pathway anti-fibrotic properties. QSYQ, a Chinese patent medicine for treating myocardial ischemia, can improve cardiac function and reduce inflammatory cell infiltration, fibrosis, and oxidative stress levels in rats with MI (Liu et al., 2024). YXFM can inhibit aging-related sick sinus syndrome (SSS) and fibrosis and regulate the PI3K/Akt/FOXO and Nrf2/HO-1 pathways (Jin and Hou, 2024, Jin et al., 2024, Zhang et al., 2021). Danqi Soft Capsule, a Chinese medicine containing Salvia miltiorrhiza Bunge and Panax notoginseng (Burkill) F. H. Chen ex C. H.), regulates cardiac fibrosis, Cx43 expression, and cell hypertrophy via the TGF-β1/Smad3 pathway, reducing the risk of arrhythmia (Ma et al., 2019). HQSML can activate SIRT3 and inhibit the TGF-β/Smad pathway to improve fibrosis (Pan et al., 2021). XYT alleviates cardiac fibrosis by activating SIRT1 to inhibit EndMT, and has also been reported to promote mitophagy via HDAC3-regulated PINK1/Parkin signaling (Chen et al., 2025, Li et al., 2025). Ginseng Dingzhi Decoction may improve fibrosis by regulating gut microbiota and mitochondrial function (Wang, Chen, Cao, Wang, & Chang, 2022). Compound Danshen Dripping Pills exert protective effects in various HF models through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms (Feng et al., 2021).

The synergistic effects of multiple components and targets are key to the efficacy of these compound formulas. For example, in QSYQ, active ingredients such as ginsenosides Rb₁ and Rg₁, and astragaloside IV, act on different targets to collectively regulate inflammation, oxidative stress, and apoptosis, forming an integrated cardioprotective network (Chen et al., 2024, Li et al., 2020, Liu et al., 2024). Furthermore, SMI may exert its anti-inflammatory and anti-fibrotic effects by inhibiting K27-linked ubiquitination of the AIM2 inflammasome (Xu et al., 2025).

In summary, ginseng-containing compound formulas, through the synergistic action of multiple components, targets, and pathways, exhibit potential in inhibiting cardiac fibrosis, improving cardiac function, and regulating the immune microenvironment (Fig. 2). This provides a theoretical basis and research direction for their further application in the clinical treatment of cardiac fibrosis.

Fig. 2.

Schematic diagram illustrating the anti-cardiac fibrosis mechanisms of ginseng and its bioactive components.

3.4. Integrated network-style overview: Linking ginsenosides to core fibrotic pathways

To improve mechanistic integration, we provide a pathway-centered synthesis that maps representative ginsenosides and ginseng-containing preparations to shared nodes e.g., TGF-β/Smad, NF-κB-driven inflammation, and oxidative stress/Nrf2 (Table 1). Notably, multiple ginsenosides converge on common upstream stress signals (ROS and inflammatory cytokines), while diverging at intermediate regulators e.g., SIRT1, AMPK, PI3K/Akt. This convergence supports the hypothesis of potential synergy when different components co-modulate complementary nodes within the same network; however, true synergy/antagonism remains largely untested in head-to-head or combination designs and should be validated experimentally e.g., isobologram analyses in CFs and factorial designs in animal models.

Table 1.

Preclinical mechanisms and anti-fibrotic effects of representative ginseng monomeric saponins in cardiac fibrosis models.

Ginseng saponins	Experimental models	Mechanistic pathways/signaling targets	Anti-fibrotic effects/functional outcomes	References
Rb1	MI/CHF/DOX cardiotoxicity	Keap1/Nrf2; SIRT1/NF-κB; TGF-β1/Smad; ERK/Akt	Reducing collagen deposition; improving remodeling and function.	Yao et al., 2022, Ren et al., 2021, Zhai et al., 2024, Zheng et al., 2017, Jiang et al., 2021, Jiang et al., 2025
Rg1	I/R injury; pressure overload; HF	Macrophage polarization; CaSR; SIRT1/PINK1/Parkin	Reducing inflammation and fibrosis markers; improving remodeling.	Lu et al., 2021, Guan et al., 2023
Rg3	Ang II hypertrophy; post-MI; HF	SIRT1/NF-κB-NLRP3; TGF-β1/Smad3; TGFBR1/Smads	Inhibiting fibroblast proliferation and collagen synthesis; improving cardiac function.	Ren et al., 2021, Lai et al., 2022
Rg2	MI/ischemia models	Akt; TGF-β1/Smad	Reducing collagen deposition; improving systolic and diastolic function.	Li et al., 2020, Wang et al., 2021
Rh2	Diabetes-related fibrosis; MI; DOX cardiotoxicity	PPARδ/STAT3; ERK-dependent pathways	Reducing CTGF and fibronectin levels; improving remodeling.	Lo et al., 2017, Duan et al., 2025, Hou et al., 2022
Re	ISO-induced fibrosis; post-MI	TGF-β1/Smad2/3; AMPK/FAK/PI3K/Akt	Reducing fibrosis; improving cardiac remodeling.	Wang et al., 2019, Yu et al., 2020
Rd	Pressure overload; post-MI	Akt/mTOR; ERK; TGF-β1	Reducing cardiac remodeling and fibrosis; modulating immune responses.	Zhang et al., 2019, Zhao et al., 2022

4. From laboratory to clinic: Key challenges on translational path

Although preclinical studies across diverse cell and animal models have yielded relatively consistent anti-fibrotic signals, translating these findings into reproducible and quantifiable clinical applications remains challenging. Key translational bottlenecks include consistency of composition and quality across products, low oral bioavailability and undefined exposure-response relationships, the rigorousness of clinical study design, and a lack of fibrosis-specific endpoints. Accordingly, this section first summarizes the available clinical evidence and stratifies studies by whether fibrosis-related endpoints are included. We then discuss major translational barriers in pharmacology and clinical research, and propose fibrosis-oriented phased trial strategies and combination-therapy approaches.

4.1. Current status of clinical research on ginseng-based medicines in cardiac fibrosis

Overall, clinical studies of ginseng-related preparations primarily use indirect indicators of remodeling or improved cardiac function-such as blood pressure, metabolic indices, symptom scales, New York Heart Association (NYHA) class, LVEF/BNP/NT-proBNP, or clinical outcomes-while biological measures directly reflecting myocardial fibrosis remain uncommon. Therefore, we categorize clinical studies into two groups based on whether fibrosis-related endpoints are included: Category A studies incorporate imaging-based measures e.g., CMR T1 mapping/ECV or LGE and collagen-turnover biomarkers; Category B studies report only symptoms, cardiac function, or risk-factor improvement and thus cannot directly demonstrate anti-fibrotic efficacy.

In the disease settings summarized below, we prioritize clear annotation of each study’s endpoints and their relevance to fibrosis, and we use cautious language when fibrosis-specific endpoints are absent.

4.1.1. Regulatory effects of ginseng-based medicines on hypertension: Mostly risk-factor improvement with limited fibrosis endpoints

Hypertension is a major risk factor for cardiac fibrosis, and controlling blood pressure is crucial for preventing and delaying its onset and progression (Lin et al., 2016, Wang et al., 2012). As a TCM, the use of ginseng in the prevention and treatment of hypertension is gaining increasing attention. Existing studies indicate that different ginseng extracts, including specific saponin components, have varied effects on blood pressure (Rhee et al., 2014).

Existing studies suggested that some ginseng extracts or saponin-enriched preparations (e.g., Rg₃-enriched KRG and Ginseol K-g₁) can reduce seated blood pressure or improve indices related to arterial stiffness and vascular tone in certain populations (Jovanovski et al., 2020, Rhee et al., 2014).

Notably, the primary outcomes of these studies focus on blood pressure and vascular function, with little or no assessment of myocardial fibrosis using imaging (e.g., CMR T1/ECV or LGE) or collagen-turnover biomarkers. Therefore, these results cannot be directly interpreted as evidence of anti-cardiac fibrotic efficacy. If hypertension-associated interstitial fibrosis is selected as the target scenario, future studies should incorporate fibrosis endpoints on top of blood pressure and anti-remodeling therapy to verify direct effects on fibrotic progression.

4.1.2. Application of ginseng-based medicines in CAD treatment: Primarily symptom-focused outcomes

Due to their pleiotropic cardiovascular protective effects, ginseng-based medicines have garnered widespread attention in the field of coronary artery disease (CAD) treatment in recent years. Clinical observations indicate a close relationship between cardiac fibrosis and the development of CAD. The partial benefits of ginsenosides and their compound formulas in improving cardiac function in CAD patients may be related to their anti-cardiac fibrosis effects. Current research in this area mainly explores a synergistic treatment model combining Western medicine (WM) with ginseng-containing TCMs.

A representative example is Xinyue Capsule (XYC), which contains American ginseng (AG) total saponins as key constituents and has been evaluated in a multicenter randomized controlled study in patients with stable CAD after PCI, with primary endpoints including cardiovascular events and quality of life (Guo et al., 2020).

In addition to XYC, other ginseng-containing preparations have also shown clinical potential. A study evaluating the efficacy of QSYQ in patients with acute coronary syndrome after percutaneous coronary intervention (PCI) indicated that QSYQ combined with Western medical treatment could reduce the risk of major adverse cardiac events including cardiac death, non-fatal MI, and urgent revascularization (Bai et al., 2024).

A phase I clinical trial of Danqi Tablets, a TCM used clinically for CAD, showed that it was well-tolerated at a single dose of 5 760 mg and at 2 160 mg twice daily for 14 d, with the most common adverse event being an increase in daily bowel movements (Gou et al., 2019).

In conclusion, although most CAD trials have focused on clinical outcomes such as major adverse cardiovascular events and quality of life, these endpoints do not directly confirm anti-fibrotic effects. Future studies should incorporate fibrosis-sensitive imaging techniques and biomarker panels to clarify whether clinical benefits are associated with modulation of fibrotic remodeling. Current evidence indicates that ginseng-containing medicines, exemplified by XYC, may offer additional cardiovascular protection when combined with standard Western therapies. However, variability in study design, sample size, follow-up duration, and component standardization necessitates further large-scale, high-quality trials to confirm efficacy, safety, and underlying mechanisms, particularly their potential role in attenuating cardiac fibrosis.

4.1.3. Application of ginseng-based medicines in DCM treatment: Metabolic endpoints dominate and fibrosis assessment is insufficient

DCM, a severe cardiovascular complication of diabetes, is primarily characterized by progressive cardiac fibrosis and impaired cardiac function (Chen and Wang, 2024, Meng et al., 2022, Zschirnt et al., 2020). In recent years, several studies have explored the role of different ginseng preparations in glycemic regulation, suggesting that ginseng-based medicines may intervene in the development of DCM through multiple pathways.

In terms of glycemic regulation, various studies have investigated the effects of different ginseng preparations. Red ginseng-related products have shown some potential for lowering blood glucose. One study found that red ginseng Cheonggukjang significantly reduced fasting blood glucose (FBG) levels in individuals with impaired fasting glucose (Shin et al., 2011). A study on Korean adults with prediabetes also showed that red ginseng extract powder (RGEP) has the potential to lower FBG (Jeong, Lee, Shim, Jang, & Kim, 2024). However, this glucose-lowering effect has not been consistently confirmed across all studies. Some research reported that ginseng and ginsenoside Re did not significantly improve β-cell function or insulin sensitivity in overweight and obese subjects with impaired glucose tolerance or newly diagnosed type 2 diabetes (Reeds et al., 2011). Additionally, a randomized clinical trial in patients with prediabetes found that hydrolyzed ginseng did not significantly reduce fasting glucose levels after six months (Bessell et al., 2020).

Besides fasting glucose, the effect of ginseng on postprandial glucose regulation has also attracted attention. Research has shown that ginseng berry saponins (Zhenyuan Capsule) can significantly reduce 2-hour postprandial glucose levels in patients with prediabetes (Gao et al., 2024a). It is noteworthy that while AG and KRG prepared by different ethanol extraction methods did not show significant differences in lowering postprandial glucose in healthy adults, the KRG-30% and AG-50% extracts did show an improvement in insulin sensitivity (De Souza, Jenkins, Jovanovski, Rahelić, & Vuksan, 2015). This suggested that ginseng extracts may indirectly regulate blood glucose by affecting insulin sensitivity.

The discussed studies largely address glycemic control and insulin sensitivity, with limited or no direct assessment of myocardial fibrotic remodeling. Moreover, results across trials are inconsistent, possibly due to heterogeneity in ginseng species, extraction methods, doses, and study populations. Hence, claims should be interpreted cautiously and not as confirmed clinical anti-fibrotic evidence.

Regarding the improvement of insulin resistance, study results are somewhat inconsistent. Supporting evidence showed that ginseng berry saponins can reduce the HOMA-IR index and increase the QUICKI index (Gao et al., 2024b). RGEP has also been shown to improve insulin resistance indicators in prediabetic populations (Jeong, Lee, Shim, Jang, & Kim, 2024). However, not all studies have demonstrated a positive effect of ginseng on insulin sensitivity; other research has not observed a significant improvement (Reeds et al., 2011). This inconsistency may be related to factors such as the type of ginseng, extraction process, dosage regimen, and characteristics of the study population.

Notably, combination therapy strategies have shown unique advantages. Studies have found that ginseng combined with viscous fiber and Salba-chia can synergistically improve glycemic control in patients with type 2 diabetes (Zurbau et al., 2021). The combination of AG and a konjac-glucomannan fiber blend (KGB) can produce a modest but clinically meaningful reduction in glycated hemoglobin and blood lipid concentrations, thereby enhancing the effectiveness of conventional therapy (Jenkins et al., 2018). These findings suggested that combining ginseng with other substances that have glucose-lowering or metabolism-improving functions may produce a synergistic effect, leading to more effective glycemic control.

It should be emphasized that most of the studies discussed above lack direct assessment of myocardial fibrosis (imaging or collagen-turnover biomarkers) and show some inconsistency across trials; thus, current evidence supporting direct anti-cardiac fibrotic effects remains insufficient. Future DCM-oriented clinical studies should incorporate key fibrosis endpoints such as CMR T1/ECV and LGE or collagen-metabolism markers on top of standard glucose-lowering and cardioprotective therapy to test whether ginseng-based interventions truly alter fibrotic remodeling.

4.1.4. Application of ginseng-based medicines in HF treatment: Most endpoints remain indirect

HF, the terminal stage of many cardiovascular diseases, is pathologically characterized by cardiac fibrosis (Chen et al., 2023, Frangogiannis, 2019). Globally, HF is a leading cause of death and hospitalization, and cardiac fibrosis, as a key pathological process in its progression, is closely associated with poor clinical outcomes (Ravassa et al., 2023). Therefore, HF populations represent a clinically reasonable scenario for evaluating potential anti-fibrotic interventions.

Clinical studies suggested that ginseng-based medicines have potential therapeutic value in improving myocardial remodeling and inhibiting cardiac fibrosis in patients with HF. A clinical study on patients with CHF showed that standardized Western medical treatment combined with SMI could effectively improve patient prognosis. The study divided 1 211 eligible CHF patients into two groups: the control group received standardized Western medical treatment plus other Chinese patent medicines or decoctions (but not SMI), while the exposure group received SMI for more than seven days in addition to the standard treatment. Analysis of the 1 047 patients who completed follow-up revealed that the SMI exposure group showed improvements in NYHA functional class, LVEF, and NT-proBNP levels. Furthermore, the rates of cardiac death and rehospitalization for HF were significantly lower in this group (Guan et al., 2022).

HF studies more closely relate to fibrosis-driven remodeling, and some include biomarker signals; however, many reports rely on surrogate endpoints (NYHA, LVEF, NT-proBNP) and are limited by non-randomized designs, short follow-up, and variable formulation quality. Robust confirmation requires randomized, double-blind trials incorporating fibrosis-specific endpoints in well-defined HF phenotypes (e.g., HFpEF with diffuse interstitial fibrosis).

YQFM, a modern preparation derived from the traditional formula Shengmai San, is widely used in the treatment of HF (Lv, Wang, Zhang, & Shang, 2022). This injection primarily contains active ingredients from P. ginseng, Ophiopogon japonicus (Linn. f.) Ker-Gawl., and Schisandra chinensis (Turcz.) Baill., with triterpenoid saponins, steroidal saponins, lignans, and flavonoids considered its key material basis for efficacy. Long-term clinical practice has confirmed the positive effects of YQFM in treating HF, with very few adverse events reported (Zhang et al., 2023). Moreover, as an adjuvant therapy, YQFM, when used with conventional treatment, significantly improved cardiac function and related indicators in patients with CHF compared to conventional treatment alone (Nie et al., 2020).

Comparative studies of various TCM injections have further highlighted the value of ginseng-containing preparations in HF treatment. A network meta-analysis showed that Huangqi Injection, Shengmai Injection, SFI, SMI, and Xinmaitong Injection, when combined with WM, were all superior to WM alone in treating HF associated with DCM-HF. The combination of Xinmaitong Injection and WM performed the best, followed by SMI and Huangqi Injection (Cao, Liu, Zhou, Chen, & Long, 2022).

In addition, oral preparations such as XYT have also shown potential in the treatment of CHF, helping to improve clinical symptoms and exercise tolerance in patients and possibly even improving long-term prognosis, though its efficacy requires support from higher-level clinical evidence (Liu et al., 2020).

Although post-MI remodeling inherently involves replacement fibrosis, the cited clinical reports mainly evaluated myocardial injury and functional recovery after PCI. They did not provide direct fibrosis imaging or histological confirmation; therefore, anti-fibrotic conclusions remain inferential. A post-MI trial with prespecified fibrosis endpoints (CMR-based LGE, T1 mapping/ECV, and validated collagen-turnover biomarkers) would be needed to test anti-fibrotic efficacy.

Overall, the currently available clinical studies of ginseng-based preparations provide mainly indirect signals (e.g., blood pressure, metabolic indices, cardiac function, or event-related outcomes) that could be compatible with anti-remodeling effects; however, direct anti-fibrotic efficacy in humans remains unproven because fibrosis-specific imaging, histology, or validated biomarkers are rarely assessed. Future randomized controlled trials should incorporate fibrosis endpoints-such as CMR T1/ECV or collagen-turnover biomarkers-on top of standard therapy and standardize treatment duration and dosing to verify direct effects on fibrotic progression.

4.1.5. Application of ginseng-based medicines in MI treatment: Replacement fibrosis is relevant but evidence still centers on short-term outcomes

Following AMI, cardiac fibrosis is the core pathological process of ventricular remodeling, which can lead to severe complications such as malignant arrhythmias and HF (Li, Xiang, & Wang, 2020). Therefore, the post-AMI remodeling phase is also an important scenario for evaluating potential anti-fibrotic interventions. Recent studies have shown that ginseng and its active components have therapeutic potential in improving cardiac function and inhibiting cardiac fibrosis and inflammation after AMI.

In existing clinical studies, SFI has been used as an adjunctive intervention in patients with AMI, often within PCI-based treatment workflows. Some reports suggested that SFI may improve indices of myocardial injury and functional recovery and may have potential implications for longer-term ventricular remodeling (Li, Xiang, & Wang, 2020). These effects may be achieved through multiple mechanisms, including inhibiting inflammatory responses, alleviating oxidative stress damage, and regulating cardiomyocyte apoptosis.

However, most such studies did not include fibrosis-specific assessments such as CMR-based fibrosis imaging (LGE or ECV) or collagen-turnover biomarkers, and their evaluations mainly emphasized acute management and short-term functional improvement. Therefore, evidence for anti-fibrotic effects and suppression of scar remodeling remains indirect. Future randomized controlled trials during the post-AMI remodeling window, with quantitative fibrosis endpoints as primary outcomes, are needed to clarify the true impact of SFI and similar preparations on fibrotic phenotypes. Fig. 3 showed ginseng-based medications have specific clinical applications in hypertension, CAD, DCM, HF, and MI.

Fig. 3.

Key challenges on translational path: From laboratory to clinic.

4.2. Pharmaceutical bottlenecks and counter-strategies

A major limitation of ginsenosides in clinical application is their generally low oral bioavailability. Saponins such as Rb₃ and Rh₂ have poor intestinal permeability due to their large molecular weight and suboptimal lipid-water partition coefficients. They are also susceptible to metabolism by gut microbiota and the hepatic first-pass effect, which severely restricts the therapeutic efficacy of oral administration (Guan & Qi, 2023). This bottleneck significantly limits their potential as oral drugs and the consistency of their clinical effects. Innovative drug delivery systems are the core strategy for overcoming this bioavailability bottleneck.

To address this challenge, researchers have developed various innovative strategies. In terms of novel delivery systems, ROS-responsive nanoparticles can achieve targeted release of ginsenoside Rg₃ at sites of high oxidative stress, such as in ischemia-reperfusion injury (Li et al., 2020). An albumin-bound nanoparticle formulation of nabCK significantly improved its solubility and liver-targeting efficiency, providing cardiac protection while ameliorating non-alcoholic fatty liver disease (Yue et al., 2023). Rb₃ encapsulated in chitosan-tripolyphosphate nanoparticles was able to more effectively target the PPARα pathway, inhibiting cardiac fibrosis by improving energy metabolism and mitochondrial function (Zhang et al., 2021). Beyond improving absorption, translational work should report standardized composition, justify dosing, and link exposure to pharmacodynamic readouts. Notably, the effective doses of key saponins summarized across animal fibrosis models in this review span a broad range (about 2.5−500 mg/kg), underscoring the need for exposure-response translation and careful human-equivalent dose considerations (Nair & Jacob, 2016) to inform clinically feasible dosing regimens.

In terms of dosage form optimization, carrier systems like liposomes and microemulsions can effectively enhance the lipid solubility and biomembrane permeability of ginsenosides. Transdermal delivery systems can bypass the first-pass effect and maintain stable plasma concentrations through slow release of the drug through the skin. Dripping pills and oral films utilize mucosal absorption to partially evade hepatic metabolism (Feng et al., 2021). Additionally, micronization technology and chemical modification have been used to improve solubility and target-binding capacity.

For acute or critically ill patients, injectable formulations like SFI can directly bypass the first-pass effect, alleviating cardiac fibrosis caused by ischemia-reperfusion injury through the activation of adenosine A receptors (Guo et al., 2022).

4.3. Pharmacological challenges and research strategies

A key pharmacological issue in the development of ginseng-based medicines is balancing the research paths of single components versus compound formulas: whether to pursue highly purified ginsenoside monomers with clear mechanisms or to preserve the holistic effect of multi-component synergy in traditional formulas. The complex composition of compound formulas presents major challenges for modernization in terms of quality control, mechanism elucidation, and therapeutic consistency (Yang et al., 2017). For example, YXFM, composed of ginseng and other herbs, can improve SSS in aging mice via the Nrf2/HO-1 pathway (Zhang et al., 2021), but its specific synergistic components and action network have not been fully elucidated. Recent work has explored simplified herbal formulas for HF with characterized bioactive ingredients and mechanisms, which may facilitate standardization and mechanistic elucidation (Chen et al., 2019).

To meet these challenges, researchers have proposed systematic research strategies. By integrating serum pharmacochemistry, network pharmacology, and multi-omics technologies, it is possible to systematically analyze the effective component groups in compound formulas and their synergistic mechanisms. For instance, using this strategy, researchers have successfully identified 12 potential quality markers (Q-markers) in QSYQ, including ginsenosides Rb₁ and Rg₁, and astragaloside IV (Liu et al., 2024).

Identifying Q-markers may help move research on multi-component formulations from descriptive characterization toward quantitative standardization. By quantitatively profiling key bioactive constituents within a formula, a Q-marker-anchored quality-control framework can be established to improve batch-to-batch consistency and the stability of pharmacological activity. For example, by integrating serum pharmacochemistry, network pharmacology, metabolomics, and cell-based assays, prior work has proposed 12 candidate Q-markers for QSYQ, including ginsenosides Rb₁ and Rg₁ (Liu et al., 2024).

Expanded discussion on single-compound strategies versus multi-component formulations: For individual ginsenosides, translational priorities include defining exposure-response relationships, characterizing myocardial (and other relevant target-tissue) distribution, and establishing mechanism-linked pharmacodynamic markers (e.g., pathway readouts reflecting target engagement in TGF-β/Smad or NF-κB signaling within relevant cell types). Because effective preclinical doses vary widely across models (approximately 2.5−500 mg/kg in the studies summarized here), future work should provide transparent dosing rationales and systematically report plasma and tissue exposures, together with human-equivalent dose considerations to support translational scaling (Nair & Jacob, 2016). For multi-component formulations, synergistic effects should be demonstrated empirically rather than assumed. Practical approaches include omics- and chemometrics-guided component deconvolution to identify minimal active sets, factorial or mixture designs to quantify synergy or antagonism among key constituents operating on shared pathways, and rigorous batch-to-batch quality control anchored by Q-markers and standardized bioactivity assays. Rare or biotransformed saponins and metabolites (e.g., nabCK and other rare ginsenosides) may represent an intermediate translational route as chemically definable entities that may still retain multi-target activity. Emerging reports on rare saponins (e.g., Mc-1, TP1) and nano-formulations suggested potential opportunities to improve potency, targeting, and exposure consistency; however, these approaches require standardized characterization, safety evaluation, and head-to-head benchmarking against parent compounds.

4.4. Clinical evidence bottlenecks and solutions

Because clinical studies of ginseng-related medicines mostly report indirect outcomes and vary widely in design, we explicitly assess each study from three perspectives: endpoint relevance to fibrosis (imaging/biomarkers vs indirect indices); key risk-of-bias domains (random sequence generation, allocation concealment, blinding, attrition, and selective reporting); and intervention quality (product standardization and the interpretability of dose and exposure). These considerations are summarized in Table 2 and in the fibrosis-relevance notes appended to each clinical subsection.

Table 2.

Summary of preclinical studies evaluating anti-fibrotic effects of various ginseng preparations in different populations and study settings.

Ginseng preparation	Study population and setting	Study design and duration	Primary endpoints, fibrosis relevance and study limitations	References
Ginseol K-g1 (ginsenoside triol-rich extract)	Adults with elevated BP	Randomized groups; 8 weeks	Reducing seated SBP/DBP; not assessing fibrosis; observing signals mainly in patients with high baseline BP; being limited by short study duration.	Jovanovski et al., 2014, Rhee et al., 2014
Rg3-enriched KRG	Healthy individuals	Randomized; acute (hours post-dose)	Reducing augmentation index and BP; not assessing fibrosis; focusing solely on acute hemodynamics.	Jovanovski et al., 2020
XYC (AG total saponins)	Stable CAD post-PCI	Multicenter RCT; 24 weeks (+follow-up)	Reducing CV events and improving QoL; not assessing fibrosis; making indirect inferences regarding anti-fibrotic effects; having variable product standardization.	Guo et al., 2020
SMI and standard therapy	CHF	Multicenter cohort/retrospective	Improving NYHA class, LVEF, NT-proBNP, and clinical outcomes; assessing fibrosis indirectly; being limited by a non-randomized design with potential confounding factors.	Guan et al., 2022
YQFM/related ginseng-containing injections	CHF	Meta-analyses/heterogeneous trials	Improving symptoms and cardiac function; using limited biomarkers; lacking fibrosis imaging or histological assessment; having heterogeneous trial quality.	Nie et al., 2020, Lv et al., 2022

Current clinical research on the anti-cardiac fibrosis effects of ginseng-based medicines has significant limitations, mainly in terms of insufficient sample sizes, a lack of randomized, double-blind, placebo-controlled designs, varied treatment durations, and inconsistent evaluation metrics. These issues result in a low level of evidence, which is insufficient to support the development of clinical guidelines. For example, while SMI can improve LVEF and LVFS in the treatment of hypertensive heart failure (Huang et al., 2023), the study was limited by its sample size. YQFM can reduce serum levels of fibrosis markers like MDA and procollagen type III N-terminal peptide (PIIINP) (Pang et al., 2017), but it lacks evaluation based on hard clinical endpoints.

To overcome these evidence bottlenecks, it is imperative to establish a systematic and rigorous clinical development pathway.

4.4.1. Phase I clinical trial design

In addition to assessing basic safety and tolerability in healthy volunteers, population pharmacokinetic studies should be actively conducted in patients with early-stage cardiac fibrosis. This would provide more accurate data on drug absorption, distribution, metabolism, and excretion in the target population, offering a direct basis for dose selection in Phase II trials. During the study, vital signs, electrocardiograms, blood counts, and liver and kidney function should be closely monitored, with a particular focus on potential toxic reactions indicated by preclinical studies (Gago Martínez et al., 2016, Mahmoud et al., 2022).

4.4.2. Phase II proof-of-concept and dose-exploration trials

At this stage, advanced imaging biomarkers such as CMR T1 mapping and ECV fraction should be fully utilized to accurately select patient populations with clear evidence of active fibrosis (Pan et al., 2023, Zschirnt et al., 2020). An adaptive trial design is recommended, allowing for adjustments to dose groups or enrollment criteria based on interim analyses to improve research efficiency. Concurrently, biological samples should be systematically collected for the discovery and validation of novel predictive biomarkers, such as circulating miRNAs and ECM degradation products.

4.4.3. Phase III confirmatory trials

Confirmatory trials should employ a composite endpoint design, integrating hard clinical endpoints (e.g., cardiovascular mortality, rehospitalization for HF), functional endpoints (LVEF, BNP, 6-minute walk distance), and fibrosis-specific endpoints (serum PIIINP, cardiac MRI ECV). These trials must be large-scale, multicenter, randomized, double-blind, placebo-controlled superiority or non-inferiority trials (Citrome et al., 2025, Zhang and Deng, 2025). For compound formulas, including an active comparator group (e.g., standard HF therapy) is highly valuable. Patients could be randomly assigned to different dose groups of the ginsenoside therapy and a placebo control group (Algotar et al., 2013).

Furthermore, special attention should be given to pharmacology in special populations. Pharmacokinetic studies specifically designed for elderly patients and those with hepatic or renal impairment are necessary to provide dose adjustment guidelines for individualized clinical use (Dotta et al., 2011, Goede and Hallek, 2007, Scicchitano et al., 2012). For example, considering that elderly patients may have reduced drug metabolism due to decreased liver and kidney function, corresponding dose adjustments would be required (Goede & Hallek, 2007).

4.4.4. Cardiac-fibrosis-focused trial scenarios and endpoints

We propose practical, ginseng-specific trial scenarios where fibrosis is a central driver and can be measured rigorously, which highlights the potential experimental designs and measurable outcomes. HFpEF with diffuse interstitial fibrosis: enroll patients with elevated ECV/T1 or validated collagen-turnover biomarker profiles; primary endpoint could be change in ECV/T1 at 6-12 months, with secondary endpoints in exercise capacity and NT-proBNP. Post-MI ventricular remodeling: enroll patients after reperfused MI with prespecified LGE scar and remote-myocardium ECV; evaluate remodeling (LV volumes) together with fibrosis metrics (LGE or ECV) and collagen biomarkers. DCM (early-stage): target patients with subclinical diastolic dysfunction plus fibrosis imaging evidence; combine metabolic and fibrosis endpoints to test whether glycemic improvement co-translates to anti-fibrotic remodeling.

Across scenarios, we recommend: standardized product characterization (for extracts/formulas), prespecified anti-fibrotic endpoints, and a priori plan for risk-of-bias control (randomization, blinding, placebo/active comparators, and protocolized co-therapies).

4.5. Clinical application strategies and practical pathways

A key issue that urgently needs to be addressed is how to safely and effectively integrate ginseng-based medicines into the current evidence-based treatment system for cardiovascular diseases and to clarify their position in the therapeutic pathway (e.g., as adjuvant therapy, alternative therapy, or for special populations).

4.5.1. Exploration of combination therapy strategies

Preclinical research provides a theoretical basis for combination therapy. Studies have shown that high-dose ginsenoside Rb₁ is comparable to the ARB losartan in terms of anti-fibrotic effects and improving cardiac function (Zheng et al., 2017). A novel synthetic ginsenoside precursor, 20S-O-Glc-DM (C20DM), has shown greater potential than metoprolol in improving left ventricular diastolic dysfunction (Guo et al., 2024). These findings supported the use of ginseng-based medicines as enhancers for existing standard therapies or as alternative options for patients who cannot tolerate standard treatments.

Future clinical research should focus on exploring the synergistic effects, safety, and optimal timing of combining ginseng-based medicines with standard HF drugs such as ACEIs, ARBs, ARNIs, and SGLT2 inhibitors. Existing preclinical evidence showed that ginsenoside Rg₁ combined with conventional therapy (including lifestyle interventions and lipid-lowering treatments) can significantly reduce the number of arterial plaques, improve inflammatory markers, and enhance quality of life (Fang et al., 2025, Xin et al., 2024), providing indirect clinical support for the combined use of ginsenosides with other drugs in cardiac fibrosis.

4.5.2. A practical path to precision medicine

Achieving precision medicine requires the discovery and validation of biomarkers that can predict therapeutic response. Studies have found that ginsenoside Rg₃ can modulate abnormal N-acetylglutamine metabolism levels in HF (Lai et al., 2022). Such metabolic markers or specific genetic features could potentially be used to identify patient populations who would benefit most from Rg₃ treatment.

In a study of SMI for hypertensive heart failure, a significant downregulation of mRNA expression levels of type I collagen, TGF-β1, and Smad2/3 was observed (Hu et al., 2023), suggesting that it inhibits cardiac fibrosis by regulating the TGF-β/Smad pathway. Meanwhile, YQFM can reduce serum levels of fibrosis and cardiac function markers such as MDA, PIIINP, NT-proBNP, and HYP (Pang et al., 2017). This reflects a shift from the traditional same treatment for the same disease approach to the modern different treatment for the same disease therapeutic concept.

Biomarkers have multiple values in drug development. They can assist in disease diagnosis, evaluate treatment efficacy, and help elucidate drug mechanisms (Gomez-Mancilla et al., 2023, Tang and Francis, 2003). Several studies have investigated the effects of ginseng-based medicines on cardiac fibrosis-related biomarkers, and the results indicate their potential to modulate the fibrotic process.

4.5.3. Systematic evaluation of drug interactions

To ensure clinical safety, it is essential to systematically evaluate the pharmacokinetic and pharmacodynamic interactions between ginsenosides and commonly used cardiovascular drugs, especially anticoagulants like warfarin and cardiac glycosides like digoxin. Clear clinical guidelines based on research evidence should be developed to prevent potential risks such as bleeding and arrhythmias (Xu et al., 2024). In clinical practice, dosage regimens must be individualized under the guidance of a physician, and patient monitoring must be enhanced.

4.5.4. Perioperative and special-context applications

Perioperative cardiac injury is a significant factor affecting patient prognosis. Ginseng-based medicines have also shown potential in mitigating perioperative cardiac fibrosis. Studies indicate that SMI protects against radiation-induced cardiac injury by inhibiting oxidative stress and structural remodeling (Xu et al., 2023a).

In the prevention and treatment of chemotherapy-induced cardiotoxicity, ginsenoside Rb₁ alleviates doxorubicin cardiotoxicity by inhibiting autophagy and ferroptosis (Zhai et al., 2024), while ginsenoside Rh₂ exerts protective effects by inhibiting apoptosis, inflammation, and pathological remodeling (Hou, Yun, Cui, & Kim, 2022).

These findings suggested that ginseng-based medicines have potential applications in perioperative cardiac protection, particularly in preventing and treating radiotherapy or chemotherapy-related cardiotoxicity. Their protective effects are primarily achieved through multiple mechanisms, including the inhibition of oxidative stress, apoptosis, autophagy, and inflammation.

5. Discussion

5.1. Key challenges for clinical translation: Selecting fibrosis endpoints

Preclinical studies consistently indicate that certain ginsenoside monomers, extracts, and ginseng-containing formulations can modulate key pathways including TGF-β/Smad, NF-κB, PI3K/Akt, and Nrf2, thereby reducing collagen deposition, suppressing fibroblast activation, and improving myocardial remodeling and function. However, substantial heterogeneity exists across disease models (e.g., ischemia, pressure overload, diabetes, and drug toxicity), dosing regimens, and endpoint selection. Effective doses span a wide range (approximately 2.5−500 mg/kg across studies summarized in this review), and therefore exposure–response relationships and clinically feasible dosing remain to be defined.

5.2. Formulation and quality standardization

By contrast, current clinical studies largely focus on indirect endpoints such as blood pressure, metabolic indices, NYHA class, LVEF, and NT-proBNP. Trials using fibrosis as a primary endpoint remain scarce, particularly randomized controlled studies incorporating quantitative CMR methods (T1 mapping/ECV and LGE) or systematic collagen-turnover biomarker panels. Thus, evidence for a definitive anti-cardiac fibrotic effect of ginseng-related medicines remains insufficient, and conclusions should be framed cautiously.

From a translational perspective, the first priority is formulation standardization and quality consistency. For extracts or multi-herb formulas, a quality-control system anchored by Q-markers should be established to define key constituent profiles, batch-to-batch consistency, and bioactivity stability. Study reports should transparently disclose product sources, manufacturing processes, and quantitative content of key components, and systems pharmacology together with experimental mixture designs should be used to validate synergistic or antagonistic relationships rather than assuming them.

A second major bottleneck is pharmacokinetics and bioavailability. Many ginsenosides showed poor oral absorption and pronounced first-pass metabolism, limiting the ability to achieve effective exposure at clinically feasible doses. Future work should systematically integrate PK/PD studies in animals and humans, establish mechanism-linked pharmacodynamic readouts (e.g., measurable markers reflecting target engagement in TGF-β/Smad activity, inflammatory cytokines, or oxidative-stress pathways), and leverage innovative delivery strategies (e.g., nanocarriers, targeted delivery, and transdermal or mucosal administration) to improve exposure consistency and target-tissue distribution. Such efforts are essential for rational dose translation and for defining treatment duration.

5.3. Prospects and feasibility of monotherapy

For clinical validation, priority should be given to patient populations in which fibrosis is a dominant, quantifiable driver of disease, such as HFpEF with diffuse interstitial fibrosis, post-reperfusion MI during the remodeling phase, and early-stage DCM. Trials should be conducted on a background of guideline-recommended standard therapy, with prespecified fibrosis endpoints as primary outcomes-such as CMR-based quantification (T1/ECV and LGE) or collagen-turnover biomarkers-while also capturing functional outcomes and safety, including systematic evaluation of drug-drug interactions with commonly used cardiovascular agents (e.g., warfarin and digoxin). Only well-designed randomized, blinded, placebo or active-controlled trials with adequate follow-up can determine whether ginseng-related medicines modify fibrotic phenotypes in humans and whether such changes are clinically meaningful.

Importantly, ginseng-derived agents are not necessarily limited to adjunctive use with standard therapy in the long term. From a drug-development and clinical-practice perspective, standardized ginseng-derived monomers or well-defined preparations have already established a replicable development path in other disease areas, providing a practical precedent for exploring monotherapy in cardiac fibrosis. For example, standardized ginsenoside Rg₃ preparations have been developed and used clinically in oncology, demonstrating that a defined ginseng monomer can be advanced into a regulated drug product. In addition, preparations based primarily on P. notoginseng total saponins (a closely related Panax species within the Araliaceae family) are widely used as independent proprietary medicines in indications such as ischemic stroke and microcirculatory disorders. Together, these examples suggested that when key active constituents are defined, quality control is robust, and dose and safety boundaries are clear, P. notoginseng-derived standardized medicines can plausibly advance toward single-agent therapy for a specific pathological process.

Building on these considerations, we propose a staged program to develop monotherapy-oriented anti-fibrotic strategies. First, exploratory studies should enroll patients with a clear fibrotic phenotype and relatively stable clinical status (e.g., HFpEF with diffuse interstitial fibrosis, post-MI patients in the remodeling phase, and early DCM) to optimize dose and treatment duration. Next, randomized controlled trials with quantitative CMR fibrosis measures as primary endpoints should test whether ginseng-based medicines can serve as the primary anti-fibrotic agent (on top of stable standard-of-care therapy) rather than only as an adjunct. In parallel, potential interactions with commonly used cardiovascular drugs (e.g., anticoagulants and antiarrhythmics) and long-term safety should be systematically evaluated.

Overall, ginseng-derived medicines offer multi-target network regulation and are increasingly amenable to industrial standardization. With improved evidence quality and rigorous dose-exposure characterization, they have strong potential to evolve into an independent anti-fibrotic therapeutic option.

CRediT authorship contribution statement

Mengtao Zhi: Literature review, Visualization, Writing – original draft. Ao Wang: Literature review, Writing – original draft, Writing – review & editing. Hailian Quan: Conceptualization, Supervision, Writing – review & editing. Lan Hong: Conceptualization, Project administration, Supervision, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.