Therapeutic Targeting of Viral Myocarditis with Natural Products and Herbal Medicines: From Immune-Inflammatory Mechanisms to Clinical Translation

Abstract

Viral myocarditis (VMC) is a heterogeneous inflammatory myocardial disease initiated by viral infection and sustained by dysregulated innate and adaptive immunity. Its progression can be viewed as a stage-dependent continuum: virus-triggered macrophage and T-cell dysregulation initiates immune-inflammatory amplification; oxidative stress and autophagy-lysosomal dysfunction further intensify myocardial injury; and these processes ultimately converge on cardiomyocyte death and fibrotic remodeling. We conducted a structured narrative review of relevant clinical and preclinical studies identified through major English- and Chinese-language databases and reference-list screening. Distinct from previous reviews that mainly catalogued individual pathways or interventions, this review integrates disease-stage-specific pathobiology, evidence hierarchy, and translational readiness within a unified framework. Among clinically evaluated interventions, Huangqi-based preparations and Qidong Yixin Oral Liquid have comparatively broader—although still low-certainty—human evidence for adjunctive improvements in symptoms, myocardial injury markers, inflammatory indices, and selected functional outcomes. By contrast, oxymatrine and berberine are supported mainly by repeated preclinical studies. Across these interventions, the most consistently implicated targets include NF-κB, NLRP3, JAK/STAT, PI3K/Akt, and TGF-β/Smad signaling. Major knowledge gaps include small and heterogeneous clinical studies, variable formulations and quality control, incomplete pharmacokinetic characterization, limited disease-stage and biomarker stratification, and scarce long-term efficacy and safety data. Future translation should prioritize standardized products, exposure-response evaluation, biomarker-guided patient selection, and rigorous multicenter randomized trials. Overall, natural products and herbal medicines should currently be regarded as promising adjunctive candidates whose clinical value depends on stronger, stage-specific, and methodologically robust evidence.

Graphical Abstract

Introduction

Viral myocarditis (VMC) can be triggered by several cardiotropic viruses and presents across a broad clinical spectrum, from mild malaise and palpitations to heart failure, malignant arrhythmias, cardiogenic shock, and sudden death.^1,2 Its course is often unpredictable: some patients recover after the acute phase, whereas others develop persistent myocardial inflammation, inflammatory cardiomyopathy, and ultimately dilated cardiomyopathy (DCM), with progressive functional decline and disability.³ Over the past 30 years, the global numbers of incident myocarditis cases and deaths have increased by approximately 66.9% and 45.9%, respectively, while age-standardized incidence, mortality, and disability-adjusted life-year rates have also risen.^4,5 The estimated incidence is 10–22 cases per 100,000 people, with a growing burden across sociodemographic regions and particular concern among adolescents and young to middle-aged adults. Diagnosis and long-term management also impose substantial healthcare and economic costs.^4,5 Collectively, these trends establish VMC as an inflammatory cardiomyopathy of increasing public-health importance.⁶

The therapeutic goals of VMC are to limit viral replication and myocardial injury, correct dysregulated immunity, suppress excessive inflammation, preserve hemodynamic and cardiac function, reduce arrhythmic and heart-failure events, and prevent progression to dilated or post-inflammatory cardiomyopathy. However, reversal of cardiomyocyte injury and prevention of ventricular remodeling remain major clinical challenges. Current treatment is largely supportive and may include guideline-directed heart-failure therapy, antiviral agents, glucocorticoids, intravenous immunoglobulin (IVIG), and immunosuppressive therapy.⁷ Antiviral efficacy is limited by the lack of pathogen-specific strategies, whereas the optimal timing, dose, and target population for immunosuppression remain uncertain. Although immunosuppressive approaches may improve inflammatory markers and selected outcomes, they may inadequately control viral replication and increase adverse events such as secondary infection, contributing to heterogeneous treatment effects.^8,9 Evidence for a prognostic benefit of IVIG is likewise inconclusive because study designs, patient populations, and endpoints vary substantially.¹⁰ Consequently, reproducible, mechanism-directed therapies for VMC remain an unmet need.¹⁰

The 2025 ESC Guidelines emphasize phenotype-based assessment, multimodal imaging, selective endomyocardial biopsy, guideline-directed management of heart failure and arrhythmias, temporary exercise restriction during active disease, and selective rather than routine empirical immunosuppression in appropriately characterized immune-mediated myocarditis.⁷ The 2020 American Heart Association scientific statement addresses fulminant myocarditis specifically and emphasizes early recognition, rapid referral to experienced centers, hemodynamic stabilization, and timely consideration of temporary mechanical circulatory support.¹¹ Emerging precision-medicine strategies integrate clinical features, cardiac magnetic resonance or biopsy findings, virological testing, circulating biomarkers, and multi-omics data to distinguish virus-persistent, immune-mediated, and remodeling-dominant phenotypes. Future biomarker-guided trials should identify treatment-responsive subgroups, define optimal intervention windows, and establish objective response criteria. Herbal medicines should therefore be evaluated as investigational adjuncts to, rather than substitutes for, contemporary standard care, using standardized formulations, biomarker-based stratification, and clinically meaningful outcomes.

High-throughput sequencing and multi-omics studies indicate that VMC arises from interacting mechanisms, including direct viral injury, innate immune activation, adaptive immune imbalance, pyroptosis, mitochondrial dysfunction, and fibrosis.¹² This interconnected network may limit the effectiveness of single-target therapy. Traditional Chinese medicine (TCM) and its bioactive constituents have therefore attracted interest because they can engage multiple components, targets, and pathways.² Preclinical and clinical studies suggest that these interventions may protect the myocardium by restoring immune homeostasis, suppressing excessive inflammation, alleviating oxidative and mitochondrial injury, and modulating apoptosis and pyroptosis.¹³ Representative formulas and compounds, including flavonoids, ginsenosides, baicalin, and quercetin, have been linked to NF-κB, the NLRP3 inflammasome, STAT3, PI3K/Akt, and TGF-β/Smad signaling, supporting a network-level mode of action.¹³ Clinically, TCM is generally used as adjunctive therapy and may improve symptoms, inflammatory biomarkers, and selected measures of cardiac function. Claims regarding prevention of chronic inflammation or progression to DCM, however, remain limited by heterogeneous study designs and low-quality evidence.¹⁴

Previous reviews have generally focused on selected immune-inflammatory pathways, individual natural compounds, or broad summaries of traditional Chinese medicine interventions, whereas disease stage, evidence source, and translational readiness have received less integrated attention. The present review adopts a disease-course-oriented framework linking viral triggering, immune-inflammatory amplification, cardiomyocyte stress, and regulated cell death, and fibrotic remodeling to stage-specific therapeutic targets. It explicitly distinguishes in vitro, in vivo, and human clinical evidence; evaluates clinical evidence certainty and translational barriers; and considers molecular phenotyping and biomarker-guided treatment. We first summarize the principal pathobiological mechanisms and then evaluate natural products and herbal medicine-based interventions according to intervention type, evidence source, and translational maturity, with the aim of identifying testable priorities for standardized clinical development.

Methodology and Evidence Assessment

This review was conducted as a structured narrative review supported by a predefined literature search. PubMed, Web of Science, Embase, and the China National Knowledge Infrastructure were searched for studies published between November 1, 2015, and November 30, 2025, using a predefined strategy adapted to the indexing rules of each database. The search concepts combined terms related to the disease, intervention, and underlying mechanisms, including “viral myocarditis,” “myocarditis,” “traditional Chinese medicine,” “integrated Chinese and Western medicine,” “proprietary Chinese medicine,” “Chinese medicine injection,” “natural products,” “herbal extracts,” “bioactive monomers,” “herbal formulas,” “immunity,” “inflammation,” “oxidative stress,” “autophagy,” “apoptosis,” “pyroptosis,” “fibrosis,” and “clinical translation.” Database searches were supplemented by manual screening of the reference lists of relevant reviews and key original studies. Eligible publications included English- or Chinese-language in vitro studies, in vivo animal studies, and human clinical investigations evaluating natural products or herbal medicine-based interventions for viral myocarditis. Studies were required to report an identifiable intervention and at least one mechanistic, efficacy, safety, or translational outcome, such as immune-inflammatory regulation, oxidative stress, autophagy, regulated cell death, myocardial injury, cardiac function, or fibrotic remodeling. Conference abstracts, conference proceedings, case reports, empirical reports without extractable study data, editorials, posters, duplicate publications, and studies with insufficient methodological or outcome information were excluded.

Evidence was synthesized according to intervention type, evidence source, and translational relevance. Cellular, animal, and human clinical evidence were explicitly distinguished. The risk of bias in randomized clinical studies was assessed using the Cochrane Risk of Bias 2 tool, where sufficient information was available. The certainty of human clinical evidence was appraised qualitatively at the intervention–outcome level using a GRADE-informed framework; because no meta-analysis was performed, these judgments should not be interpreted as a formal quantitative GRADE synthesis. Randomized evidence was initially considered high certainty and was downgraded, where appropriate, for risk of bias, inconsistency, indirectness, imprecision, and publication bias, whereas non-randomized evidence was initially considered low certainty and was further downgraded when warranted. Interventions supported exclusively by cellular or animal studies were designated “not applicable—preclinical evidence only” rather than assigned a clinical GRADE rating.

Immune-Inflammatory Pathogenesis of Viral Myocarditis

Understanding of VMC pathogenesis has evolved from a model centered on direct viral injury to a multilayered framework involving immune dysregulation, altered cell fate, and maladaptive tissue remodeling. In 1956, Kibrick isolated Coxsackie group B virus from a child with acute heart failure, providing early human evidence of virus-mediated myocardial injury.¹⁵ Subsequent animal studies showed that viral replication and viral proteins disrupt cardiomyocyte integrity, causing lysis, necrosis, and acute cardiac dysfunction. Attention later shifted toward host immunity. In 1974, Woodruff and Woodruff reported that T-cell depletion markedly improved survival without substantially reducing viral load, indicating that outcome depends on the host immune response as well as viral virulence.¹⁶ Observations during the 1980s of persistent inflammation after viral clearance further implicated adaptive immunity in delayed injury. In 1987, Rose proposed that molecular mimicry between viral antigens and cardiac proteins could sustain cross-reactive autoimmunity and promote progression to chronic myocarditis and DCM.¹⁷

The classical three-phase model—viral replication, immune response, and chronic remodeling—remains a useful conceptual framework,¹⁸ but current evidence supports a more detailed mechanistic continuum. VMC involves not only viral cytotoxicity and inflammation but also disrupted proteostasis, mitochondrial and metabolic dysfunction, regulated cell death, and persistent profibrotic signaling.^19,20 These processes interact across time and tissue compartments, forming a continuum of viral triggering, immune amplification, cumulative cellular injury, and maladaptive remodeling that helps explain heterogeneous clinical phenotypes and long-term outcomes.

Accordingly, the mechanisms discussed in this review are not assigned equal pathogenic weight. We prioritize virus-triggered immune dysregulation-particularly macrophage and T-cell imbalance and the associated inflammatory amplification-as the central mechanistic axis of VMC. Oxidative stress and autophagy-lysosomal dysfunction are considered major amplifying processes, programmed cell-death pathways represent downstream effectors of cardiomyocyte loss, and fibrosis constitutes the principal structural outcome linking persistent inflammation to chronic cardiomyopathy.

Innate and Adaptive Immune Dysregulation

Macrophages

The histopathology of VMC includes interstitial inflammatory infiltration, cardiomyocyte necrosis, and tissue edema. A central immunopathological feature is the dysregulated recruitment and phenotypic transition of monocytes and macrophages (Figure 1). Viral components and damage-associated molecular patterns (DAMPs) activate local pattern-recognition receptors (PRRs), increasing CCL2/CCL7 and adhesion molecules such as ICAM and VCAM and thereby promoting macrophage influx.²¹ During the acute phase, infiltrating macrophages adopt predominantly pro-inflammatory phenotypes. Activation of NF-κB and the NLRP3 inflammasome increases TNF-α, IL-1β, IL-6, IL-12, MMP-9, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), establishing a major axis of acute myocardial injury.^22,23

Figure 1.

Macrophage- and T-cell-mediated immune cascades in viral myocarditis.

In addition to clearing necrotic debris, pro-inflammatory macrophages sustain a “recruitment–amplification” circuit by continuously secreting cytokines and chemokines, thereby aggravating structural injury.²⁴ Early in disease, Ly6Chigh macrophages predominate and contribute to immune-mediated damage while also participating in viral control.^25,26 In the Coxsackievirus B3 (CVB3) model, NLRP3-dependent overproduction of interleukin (IL)-1β amplifies inflammatory injury, and increased microRNA (miR)-223 and miR-19b-3p enhance NF-κB activity and promote TNF-α release, establishing a pro-inflammatory positive-feedback loop.^27–29 MMP-9 acts downstream to promote extracellular matrix degradation and inflammatory cell migration, and to modulate the expression of multiple inflammatory mediators, thereby shaping local inflammatory intensity and the immune microenvironment.³⁰

A prolonged disease course is often driven by defective inflammatory resolution, persistent proinflammatory signaling, impaired switching between proinflammatory and repair-associated phenotypes, and delayed engagement of reparative programs, ultimately increasing the risk of fibrosis. In later stages, Ly6Clow macrophages that are typically biased toward repair are expected to facilitate inflammatory dampening and structural remodeling. However, under conditions of sustained pro-inflammation, their polarization and reparative effects are insufficient, allowing maladaptive remodeling to progress.^25,26 Mechanistically, sustained inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) activates extracellular signal-regulated kinase 1/2 (ERK1/2; p44/42 mitogen-activated protein kinase (MAPK)) and connective tissue growth factor (CTGF) signaling in fibroblasts, promoting proliferation and collagen deposition. Additionally, vitamin D-related osteopontin (OPN)-ERK-ETS-like protein 1 (Elk1) and phosphoinositide 3-kinase (PI3K) signaling cascades enhance type I collagen expression and accelerate matrix remodeling and fibrotic consolidation.^31–33

Recent studies have partitioned macrophage responses into potentially targetable modules. The methylenetetrahydrofolate dehydrogenase 2 (MTHFD2)–Ras-proximate-1 (Rap1) axis supports monocyte–macrophage homeostasis, and its loss promotes the accumulation of recruited macrophages and exacerbates tissue injury.³⁴ In parallel, the secretion of secreted phosphoprotein 1 (SPP1) by C–C chemokine receptor 2 (CCR2)^+-derived Spp1^+ macrophages activates fibroblasts and upregulates CCL2/CCL7, reinforcing persistent recruitment in a closed-loop amplification circuit.³⁵ In contrast, pathways that promote repair-associated polarization may be protective. IL-33 induces ST2L^+ macrophages and augments IL-4 associated reparative responses. Modulation of the ILF2/ILF3-miR-192 axis and inhibition of IL-1 receptor–associated kinase 1 (IRAK1) have also been reported to enhance repair-like polarization and increase the release of IL-10, arginase-1 (Arg1), and other mediators.^36,37 Finally, the vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR3) axis promotes cardiac lymphangiogenesis, and may facilitate inflammatory clearance and functional recovery.^38,39

T Cells

VMC is an infection-triggered, immune-mediated myocardial disease in which T cells are major effectors (Figure 1). Viral invasion rapidly activates innate immunity through Toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor (NLR) pathways. The resulting IL-1-family signals and changes in antigen presentation and costimulation promote T-cell differentiation and expansion.^40–43 Early T-cell responses may restrict viral replication, but the severity and timing of these responses can become more important determinants of peak injury and long-term outcome than direct viral cytotoxicity alone.^44,45

CD4+ T cells undergo a phase-dependent shift in effector programs. In the acute stage, the T helper 1 (Th1)/Th17 axis predominates; upregulation of interferon-γ (IFN-γ) and IL-17 facilitates inflammatory trafficking into affected foci and amplifies tissue injury.^46–48 An excessively strong Th1 response can sustain co-stimulatory signaling and downstream activation circuits, thereby prolonging immunopathology even after viral replication declines.^49,50 In parallel, Th17 signaling via the signal transducer and activator of transcription 3 (STAT3) retinoic acid receptor-related orphan receptor-γt (RORγt) pathway enhances the production of IL-17 and IL-22, and promotes B-cell activation and anti-cardiac autoantibody generation, driving reciprocal amplification between cellular and humoral immunity.^51,52 During recovery, the immune milieu typically shifts toward Th2 and regulatory T cells (Treg); Th2 cells facilitate resolution and repair through IL-4, IL-5, and IL-13, whereas Tregs restrain inflammation largely via IL-10 and transforming growth factor (TGF)-β.^53–55 Consistent with this, the cholinergic anti-inflammatory pathway (CAP), which acts through the α7 nicotinic acetylcholine receptor (α7nAChR), has been implicated in limiting Th1/Th17 dominance, suggesting a potential “immune brake” node.⁵⁶ Notably, persistent residency of autoreactive CD4+ T cells can maintain the production of IFN-γ and IL-17A, driving chronic inflammation and fibrosis and is associated with progression to DCM.⁵⁷

CD8+ T cells expand during the acute phase and eliminate infected cells through perforin and granzyme B, but this cytotoxic response can also induce cardiomyocyte apoptosis and necrosis.⁵⁸ In severe disease, an IL-18-driven CD57+CD8+ subset shows enhanced cytotoxicity, whereas IL-18 blockade improves cardiac function.⁵⁹ The CXCL12/CXCR4 axis also recruits and activates CD8+ T cells; CXCR4 blockade or CD8+ T-cell depletion reduces inflammation and tissue injury.⁶⁰ In addition, Th17-derived IL-21 promotes CD8+ T-cell expansion and IFN-γ production through the IL-21 receptor, indicating coordinated amplification of CD4+ and CD8+ effector responses.^61,62

Neutrophils

Neutrophils are among the earliest innate immune cells recruited to the myocardium in VMC and exert stage-dependent effects (Figure 2). During the initial phase, they contribute to viral restriction and immune-cell recruitment, but during inflammatory amplification, they can become major mediators of tissue injury.⁶³ In the first days after infection, neutrophil phagocytosis and chemokine release recruit myeloid and lymphoid cells and may transiently limit viral spread; myocardial infiltration peaks at approximately one week. Early inhibition of neutrophil recruitment reduces necrosis, monocyte entry, and Ly6C+ inflammatory macrophage differentiation, whereas later depletion provides limited benefit. These findings suggest that neutrophils shape the early disease trajectory and the subsequent inflammatory network.^64–66

Figure 2.

Immune-effector network mediated by B cells, natural killer cells, neutrophils, and the complement system in viral myocarditis.

Neutrophil extracellular trap (NET) formation is a major injury-amplifying mechanism. Cardiac neutrophils generate abundant NETs, accompanied by increased myeloperoxidase-DNA complexes and citrullinated histone H3. NET components can directly damage cellular structures and amplify IL-1β, IL-6, and TNF-α signaling through TLR2/4/9 and NLRP3. NET-derived DNA and histones also stimulate macrophages, creating a neutrophil-NET-macrophage positive-feedback loop that accelerates necrosis and remodeling.^67,68

In addition, the cardiac microenvironment reprograms neutrophils into a CXCL2⁺/CXCL3⁺ highly pro-inflammatory subpopulation that releases TNF, IL-1, and S100A8/A9, and establishes a self-recruitment gradient through CXCL2/3-CXCR2, promoting self-enhanced infiltrate accumulation. CXCR2 blockade reduces infiltration and improves inflammation and cardiac function.⁶⁴ Under CVB3-associated conditions, neutrophils show enhanced adhesion, pro-inflammatory factor release, and prolonged survival via TLR8-NF-κB, thereby expanding myeloid mobilization. Meanwhile, increased reactive oxygen species (ROS) generation (eg, via NOX2) and degranulation of neutrophil elastase (NE), MPO, and MMPs provide antimicrobial pressure, but also impose oxidative/proteolytic overload, disrupt the extracellular matrix (ECM), promote cell death, and accelerate fibrosis.^66,67

Natural Killer (NK) Cells

In CVB3-induced VMC, natural killer (NK) cells are mobilized early, and their antiviral activity is mediated primarily by interferon-γ (IFN-γ) rather than direct cytotoxicity (Figure 2). Although CVB3 infection may not markedly increase target-cell susceptibility to NK-cell killing, recognition of infection rapidly increases IFN-γ secretion, which is further enhanced by IL-2 and may limit myocardial injury during early viral replication.⁶⁹ The CXCL10 axis links local myocardial signaling to NK-cell recruitment: IFN-γ induces cardiomyocyte CXCL10 expression, while recruited NK cells release additional IFN-γ and reinforce the antiviral response.⁷⁰ This protective effect appears to be concentrated in the early phase and has less influence on peak inflammation or late structural remodeling.

NK cell activation thresholds are finely regulated by the Forkhead box O3 (FOXO3) axis, and Foxo3 deficiency enhances NKp46-related signaling and increases the proportion of effector NKs, accompanied by an increase in IFN-γ release. In contrast, upregulation of FOXO3 activity by PI3K-Akt inhibits IFN-γ production and degranulation, leading to delayed viral clearance and aggravation of the myocarditis phenotype^71–73

In addition to antiviral effects, NK cells may also be involved in inflammatory limitation, suppressing excessive inflammation, and reducing the risk of fibrosis by influencing eosinophil, T-cell, and monocyte-macrophage responses.⁷⁴ The net effect is governed by the microenvironment; for example, myeloid-derived suppressor cells (MDSCs) downregulate NK effector molecules/receptors and remodel cytokine profiles, thereby influencing viral clearance and inflammatory load.^75–78

B Cells

B cells are important cardiac immune cells and contribute to the transition from acute inflammation to chronic remodeling (Figure 2). Beyond antibody production, they present antigens and secrete cytokines, thereby converting local innate signals into adaptive immune responses that influence injury severity and resolution.^79,80 Early after infection, DAMP-dependent activation promotes B-cell expansion and myocardial infiltration, with increased major histocompatibility complex class II (MHC-II) and costimulatory molecules such as CD40 and CD80/86, thereby enhancing T-cell priming. In animal models, B-cell depletion attenuates myocardial pathology, whereas reconstitution partially restores inflammation, supporting a pathogenic role during acute disease.⁸¹

In the pro-inflammatory pathway, B cells secrete TNF-α, IL-6, and IFN-γ, which drive Th1/Th17 bias and enhance cytotoxic T-cell effects, while inhibiting macrophage conversion to a repair-like phenotype, maintaining a pro-inflammatory myeloid milieu, and exacerbating tissue damage.⁸² The neural-immune axis “regulates” the intensity of its effects, and downregulation of B-cell α7nAChR during VMC correlates with enhanced antigen presentation, increased proinflammatory release, and elevated Th17 induction. Activation of α7nAChR inhibits NF-κB and regulates the interaction between JAK2/STAT3 and PI3K/STAT3, whereas activation of α7nAChR inhibits NF-κB and regulates JAK2/STAT3. STAT3 and PI3K/Akt diminish pro-inflammatory effects and limit disease progression.⁸⁰

B-cells are also involved in immune tolerance and inflammatory responses. Nonselective removal of B cells results in decreased Tregs and decreased FoxP3/TGF-β, suggesting that overall removal may disrupt the immune brake and exacerbate injury.⁸³ IL-10⁺ regulatory B cells (B10/Breg), a key protective subpopulation, inhibit Th1/Th17 and downregulate T-bet and RORγt via IL-10, thereby alleviating inflammation and improving outcomes.^84–87 IL-10 also inhibits fibroblast activation/migration and reduces collagen deposition, suggesting that it may be involved in limiting fibrotic remodeling.^88,89

Complement Activation

In CVB3-induced VMC, complement can shift from an early defensive response to an amplifier of tissue injury, often through sustained activation of the classical pathway (Figure 2). Transient increases in C4 and C3 are followed by rapid consumption, whereas persistent C4b deposition indicates ongoing complement activation.⁹⁰ Complement activation is also linked to ferroptosis. The transferrin receptor (TFRC) promotes C4 cleavage and interacts with C3, reinforcing complement signaling and intracellular iron accumulation in a positive-feedback loop. Disruption of the C3/C4 axis or inhibition of ferroptosis partially reverses this phenotype, suggesting that complement may act upstream of the ferroptotic injury network.⁹⁰

Viruses may further exacerbate terminal injury by weakening complement inhibitory barriers. CVB3-associated DAMP release can enhance complement initiation, and the deposition of the membrane attack complex (MAC; C5b-9) mediates membrane injury. Viral proteases 2A/3C can cleave CD55 and CD59, deregulating MAC control and rendering cardiomyocytes more vulnerable to complement-mediated damage.⁹¹ Although complement receptor CR1/2 deficiency does not significantly affect viral clearance, it impairs immune complex processing, leading to macrophage aggregation, IL-1β excess, and premature fibrosis, as well as an increased risk of progression to dilated cardiomyopathy, suggesting that the key impact of complement on outcome lies more in the control of inflammatory homeostasis and sedimentary load.^92,93

Non-Immune Mechanisms Contributing to Myocardial Injury and Remodeling

Oxidative Stress

Viral infection disrupts cardiomyocyte redox and energy homeostasis by increasing mitochondrial and NADPH oxidase-derived reactive oxygen species (ROS), impairing electron transport and membrane potential, and activating endoplasmic reticulum stress. Excess ROS damages mitochondrial DNA and membranes, releases damage-associated molecular patterns, and reinforces NF-κB-dependent inflammation and apoptosis, whereas reduced superoxide dismutase, catalase, and glutathione peroxidase activity weakens endogenous antioxidant defense.^94–96 Thus, oxidative stress functions as an interconnected amplifier of inflammatory injury, mitochondrial dysfunction, and cell death rather than as an isolated pathway (Figure 3).

Figure 3.

Oxidative-stress pathways and amplification networks in viral myocarditis. In the figure, ↑ indicates an increase, whereas ↓ indicates a decrease. Specifically, MDA is increased, whereas SOD, CAT, and GPx are decreased.

Autophagy-Lysosomal Dysregulation

Coxsackievirus B3 remodels the autophagy-lysosomal system in a stage-dependent manner: it expands the autophagosome pool while impairing autophagosome-lysosome fusion, lysosomal biogenesis, and selective cargo clearance, thereby creating a replication-permissive environment.^97–100 Viral proteases disrupt key initiation, fusion, and receptor proteins, whereas impaired mitophagy promotes the accumulation of damaged mitochondria, oxidative stress, and inflammasome activation. Autophagy may therefore support early stress adaptation and antiviral defense but become pathogenic when flux is incomplete or hijacked by the virus; therapeutic strategies should restore balanced flux rather than simply increase or suppress autophagy (Figure 4).

Figure 4.

Key pathways and regulatory nodes of autophagy reprogramming in viral myocarditis.

Apoptosis and Pyroptosis

Cardiomyocyte loss in viral myocarditis reflects interacting death-receptor, mitochondrial, and inflammatory cell-death pathways. Coxsackievirus B3 sensitizes cardiomyocytes to Fas/Fas ligand signaling and disrupts PI3K/mTOR, MAPK, BCL-2 family, and caspase networks, while oxidative stress and inflammasome activation link apoptosis with pyroptotic injury.^101–103 Regulatory microRNAs and stress-response proteins further modify the death threshold, but most evidence remains preclinical. Accordingly, intervention should limit excessive cell death while preserving antiviral clearance, with therapeutic timing determined by disease stage (Figure 5).

Figure 5.

Regulatory pathways linking cardiomyocyte apoptosis with autophagy, inflammatory signaling, and related cell-death crosstalk in viral myocarditis. In the figure, ↓ denotes downregulation of Dusp1.

Fibrosis and Adverse Remodeling

Persistent inflammation and cardiomyocyte loss activate cardiac fibroblasts and drive extracellular matrix deposition, linking acute viral myocarditis to dilated cardiomyopathy and chronic heart failure. TGF-β/Smad signaling is the central profibrotic axis, reinforced by macrophage-derived SPP1, IL-6, CXCL4/CXCR3B, and reciprocal fibroblast-immune signaling.^35,104,105 Although fibrosis initially stabilizes injured tissue, sustained activation increases collagen accumulation, reduces ventricular compliance, and establishes maladaptive remodeling. Therefore, antifibrotic interventions should target persistent inflammatory-mesenchymal crosstalk during the subacute or remodeling phase rather than indiscriminately suppress early repair (Figure 6).

Figure 6.

Principal mechanisms of myocardial fibrosis after viral myocarditis.

Taken together, the central mechanistic sequence of VMC can be summarized as viral triggering, immune-inflammatory amplification, oxidative and organelle stress, cardiomyocyte death, and fibrotic remodeling; the therapeutic relevance of individual pathways should therefore be interpreted according to their position within this stage-dependent continuum.

Clinical Evidence for Herbal Medicine-Based Interventions in Viral Myocarditis

Within the TCM framework, VMC is considered a dynamic disorder with both deficiency and excess patterns. Heat-toxin features are thought to predominate in the acute phase, whereas qi-yin deficiency becomes more prominent later; phlegm retention and blood stasis may persist throughout the disease course. Treatment principles therefore include clearing heat and toxins, replenishing qi, nourishing yin, resolving phlegm, promoting blood circulation, and restoring the pulse. Clinical syndrome-differentiation studies describe stage-related patterns such as heat-toxin invasion of the heart, yang collapse with qi depletion, qi deficiency, and phlegm-blood stasis obstruction, providing a basis for individualized treatment. Contemporary clinical studies have mainly evaluated compound formulas, proprietary Chinese medicines, and injectable preparations. As summarized in Table 1 and Supplementary Table 1, these interventions may provide adjunctive benefits for symptoms, myocardial injury biomarkers, inflammation, cardiac function, and rhythm-related outcomes.

Table 1.

Representative Human Clinical Studies of Herbal Medicine-Based Interventions for Viral Myocarditis

No.	Intervention	Dosage	Clinical Outcomes	Mechanistic Outcomes
1	Zhigancao Decoction106–108	Rehmannia (Sheng Dihuang) 50 g, Ginseng (Renshen), Hemp seed (Huomaren) each 30 g, Licorice (Zhi Gancao), Cassia twig (Guizhi), Ophiopogon (Maidong) each 20 g, Donkey-hide gelatin (Ejiao), Chinese jujube (Dazao) each 15 g, Fresh ginger (Shengjiang)10 g. Decoct in water, take in two divided doses (morning and evening), 1 decoction daily	Clinical overall response rate↑, TCM syndrome scores↓, AST↓, CK↓, CK-MB↓, NT-proBNP↓, LDH↓, cTnI↓	SOD↑, hs-CRP↓, TNF-α↓, IL-6↓, MDA↓
2	Shuxin Tongmai Decoction109–111	Astragalus (Huangqi) 20 g, American ginseng (Xiyangshen) 15 g, Salvia (Danshen) 15 g, Chinese angelica (Danggui) 10 g, Szechuan lovage (Chuanxiong) 10 g, Ophiopogon (Maidong) 10 g, Honeysuckle (Jinyinhua) 10 g, Forsythia (Lianqiao) 10 g, Licorice (Gancao) 6 g. Decoct in water, take in two divided doses (morning and evening), 1 decoction daily	Clinical overall response rate↑, ECG recovery rate↑, LVEF↑, CK-MB↓, LDH↓, AST↓, cTnT↓, cTnI↓, LVEDV↓, LVESV↓	SOD↑, Bcl-2↑, IL-8↓, IL-21↓, IL-17↓, IL-23↓, AOPP↓, MDA↓, IL-1β↓, IL-22↓, TNF-α↓, Beclin-1↓, LC3-II↓, caspase-3↓
3	Huangqi Granules112–116	4 g/time, 1 time/day, 8 g/time, 2 times/day, 4 g/time, 2 times/day, 8 g/time, 2 times/day, 10mg/kg/time, 3 times/day	Clinical overall response rate ↑, ECG recovery rate ↑, SV↑, LVEF↑, CO↑, CK↓, LDH↓, CK-MB↓, cTnI↓, cTnT↓	CD3+↑, CD4+↑, CD4+/CD8+↑, CD8+↓, IL-4↑, miR-133↑,miR-155↓, TNF-α↓, IL-6↓, IL-17↓, IFN-γ↓
4	Qidong Yixin Oral Liquid117–120	20 mL/time, 3 times/day, 20 mL/time, 3 times/day, 20 mL/time, 3 times/day, 5~10 mL/time, 3 times/day	Clinical overall response rate↑, ECG recovery rate↑, E/A↑, LVEDD↓, LVESD↓, LVEF↑, AST↓, CK↓, LDH↓, CK-MB↓, cTnI↓	CD3+↑, CD4+↑, CD4+/CD8+↑, CD8+↓, IL-10↑, TNF-α↓, IL-2↓, IL-6↓, IL-18↓, hs-CRP↓
5	Breviscapine Injection121	20 mL/time, 1 time/day	Clinical overall response rate↑, CK↓, AST↓, LDH↓	SOD↑, GST↑, NO↓, TNF-α↓, IL-6↓
6	Xiangdan Injection122	15 mL/time, 1 time/day	Clinical overall response rate↑, LVEF↑, SV↑, AST↓, CK↓, CK-MB↓, LDH↓	IgA↑, IgG↑, Th17↓, Th17/Treg↓, SOD↑, GSH↑, MDA↓

Notes: ↑, increased or improved; ↓, decreased or reduced; +, positive or increased according to the original study; ~, range. Detailed clinical evidence is provided in Supplementary Table 1.

The human evidence base comprised 25 full-text controlled reports (aggregate n = 2,078; individual samples n = 60–138): 22 reports described randomized allocation, and three used nonrandomized allocation. Treatment or follow-up lasted 7 days to 8 weeks, and the studies were single-center or apparently single-center as reported. Most trials were open label, relied on short-term composite response or surrogate outcomes, and provided limited information on allocation concealment and blinding. Accordingly, the qualitative GRADE-informed certainty was generally low for biomarker/function outcomes and very low for composite clinical-response and safety outcomes (Supplementary Tables 3 and 4).

TCM Compound Formula

Zhigancao Decoction (ZGCD), first described in Zhang Zhongjing’s Treatise on Typhoid Fever, contains Zhigancao, Gui Zhi, Ginseng, Maidong, Colla Corii Asini, Radix et Rhizoma Pinelliae, Ginger, and Jujube and was traditionally decocted in huangjiu. It is used for palpitations and dysrhythmia attributed to combined qi-yin deficiency and inadequate nourishment of the heart and vessels after external infection. In VMC, its proposed role centers on rhythm stabilization and myocardial protection through modulation of inflammation and oxidative stress. Systematic reviews and pharmacological studies support antiarrhythmic, anti-inflammatory, and anti-apoptotic effects, providing a biological rationale for clinical evaluation.^123–125 Some randomized studies report that adding ZGCD to conventional supportive therapy improves overall response and TCM syndrome scores.^106,107 Reported biomarker changes include lower indices of myocardial injury, cardiac load, inflammation, and lipid peroxidation, together with improved antioxidant capacity, although these findings remain based on limited studies.^106,107 Combination with trimetazidine has also been associated with a higher overall response rate, suggesting a possible complementary effect that requires confirmation in more rigorous trials.¹⁰⁸

Shuxin Tongmai Decoction (SXTMD) is commonly used clinically with the principles of benefiting qi and nourishing yin, activating blood, and clearing toxins/evil. Randomized studies have reported improved overall response and electrocardiographic outcomes when SXTMD was added to supportive or metabolic therapies, accompanied by reductions in creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and troponin, lower TNF-α, higher SOD, and reduced malondialdehyde and advanced oxidation protein products, consistent with inflammation suppression and oxidative stress correction.¹⁰⁹ Cardiac magnetic resonance (CMR) analyses suggest improved ventricular function and reduced volume load, including increased left ventricular ejection fraction (LVEF), decreased left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), in alignment with biomarker improvements.¹¹⁰ Mechanistic reports suggest modulation of autophagy/apoptosis (eg, downregulation of Beclin-1, LC3-II, and caspase-3; upregulation of Bcl-2) and reduced inflammatory factors.¹¹¹

Yiqi Jiedu Decoction (YQJDD) is a multicomponent formula investigated as an adjunct to conventional treatment for VMC. Its ingredients combine qi-supporting, yin-nourishing, circulation-promoting, and heat-toxin-clearing components. Two small randomized controlled studies reported higher short-term composite response rates and improvements in symptoms, myocardial-enzyme profiles, and ventricular functional indices. One study reported lower IFN-γ and higher IL-4, while the other reported reductions in IL-6 and IL-8; adverse events were mild and did not differ significantly between groups.^126,127 Because both studies were short, single-center reports that relied largely on surrogate outcomes, these findings support further investigation but do not establish clinical efficacy.

Guizhi Longgu Muli Decoction is recorded in the Synopsis of the Golden Chamber and has been investigated as an adjunctive formula for palpitations and myocardial injury in VMC. Experimental evidence for constituent actions includes cinnamaldehyde-associated reductions in CVB3 load and NF-κB signaling and glycyrrhizin-associated attenuation of inflammatory injury;^128,129 broader preclinical reports suggest possible effects on inflammatory infiltration and collagen deposition.^130,131 Human evidence, however, is limited to one nonrandomized controlled study (n = 60), which reported improvements in TCM symptom and ECG response measures and reductions in myocardial enzymes and inflammatory cytokines.¹³² The nonrandom allocation, short follow-up, and surrogate endpoints confer high risk of bias and very-low-certainty evidence.

Shenfu Yangrong Decoction combines qi-supporting and yang-warming herbs with yin-nourishing, blood-activating, and phlegm-resolving components.¹³³ Because processed Aconitum contains potentially cardiotoxic diterpenoid alkaloids, standardized processing, dose control, and clinical monitoring are essential.^134,135 Experimental studies of constituents such as schisandrin B suggest possible suppression of TLR/NF-κB-related inflammation, oxidative stress, and apoptosis.^136,137 One small randomized trial (n = 100) reported a higher composite response rate, lower cTnI and H-FABP, reduced IL-17 and NF-κB, and increased IL-27 when the formula was added to conventional treatment.¹³⁸ These short-term findings require independent replication and do not resolve formulation-specific safety.

Shengmai Xianxiong Decoction combines Shengmai Decoction with Xiao Xianxiong Decoction. The first component is traditionally used to support qi and yin, whereas the second includes Coptis, Pinellia, and Trichosanthes fruit and is used to address phlegm-heat and chest discomfort. Experimental literature provides a rationale involving redox, inflammatory, and antiviral pathways.^139–142 In one small randomized study, adding the formula to conventional treatment reduced cTnI and improved peripheral T-cell subset indices.¹⁴³ These surrogate findings are preliminary and should not be interpreted as proof of clinical benefit.

Chinese Patent Medicine

Huangqi Granules (HQG) are prepared from the dried root of Astragalus membranaceus or A. mongholicus and contain saponins, flavonoids, and polysaccharides.^144–146 Five controlled reports (aggregate n = 377; four randomized and one nonrandomized) evaluated HQG as an adjunct in pediatric VMC. Reported short-term changes included lower myocardial injury and inflammatory markers, higher CD3⁺ and CD4⁺ indices, lower IFN-γ and higher IL-4, and in some studies better ECG or ventricular-function measures.^112–116 The studies used heterogeneous doses and co-interventions, and one study used nonrandom allocation; consequently, the apparent signals remain low- or very-low-certainty evidence.

Wenxin granules are commonly used as an antiarrhythmic proprietary Chinese medicine for palpitations, chest tightness, and shortness of breath. VMC is often associated with inflammatory myocardial injury and electrophysiological instability (eg, premature beats and palpitations), and is therefore more suitable for use as an adjunct to conventional supportive therapy for symptomatic improvement and rhythmic vulnerability. A 2024 randomized controlled study reported that a 4-week combination of sodium creatine phosphate increased overall efficacy, improved LV-Tei and RV-Tei, downregulated CK-MB, high mobility group box 1 (HMGB1), and IL-37, and upregulated adropin, suggesting that inflammation-related injuries were reduced and cardiac function improved.¹⁴⁷ The systematic evaluation included 49 RCTs (two of which were VMC studies), and the combined analysis supported the superiority of the combination over conventional therapy; however, the quality of evidence and safety reports remain limited and need to be validated by high-quality trials.¹⁴⁸ Mechanistic studies and reviews suggest that the potential effects may be related to anti-inflammatory and antioxidant properties, improvement of endothelial function and vasodilation, inhibition of apoptosis, and attenuation of ischemia and fibrotic remodeling.^149,150

Qidong Yixin Oral Liquid is a multicomponent proprietary preparation used adjunctively in VMC.¹⁵¹ Four short-term randomized reports (aggregate n = 334) described improvements in composite or ECG response, myocardial injury markers, T-cell subsets, and inflammatory mediators when the preparation was added to conventional or supportive therapy.^117–120 One report also described improved LVEF and reduced ventricular dimensions. Adverse events were generally mild, but reporting was incomplete. Variation in co-interventions and outcome definitions, reliance on surrogate endpoints, and the absence of long-term follow-up limit clinical interpretation.

Huangqi Oral Liquid is an Astragalus-based preparation containing reported quality markers such as calycosin, calycosin-7-glucoside, and astragaloside IV. In one randomized, placebo-controlled pediatric study (n = 68), the preparation was associated with fewer arrhythmias, faster ECG and symptom recovery, shorter hospitalization, and improvements in myocardial injury and short-term cardiac-function measures. Mechanistic findings included reduced miR-146b and miR-155, reduced RORγt, increased FoxP3, IL-10, and TGF-β, and lower IL-17 and IL-21.¹⁵² This single small trial provides a mechanistic signal but remains insufficient to establish efficacy or long-term safety.

TCM Injections

Breviscapine Injection is prepared from total flavonoids of Erigeron breviscapus, with scutellarin as the principal constituent.¹⁵³ One nonrandomized controlled study (n = 82) reported that adjunctive treatment improved a composite response and reduced myocardial enzymes, TNF-α, IL-6, and nitric oxide while increasing SOD and glutathione S-transferase.¹²¹ Because allocation was nonrandom and outcomes were short-term and predominantly surrogate, the evidence is at high risk of bias and very low certainty; absence of a detected safety signal does not establish safety.

Xiangdan Injection (XDI) contains extracts of Salvia miltiorrhiza and Dalbergia odorifera and is used to improve microcirculatory perfusion.¹⁵⁴ In one randomized study (n = 80), XDI added to conventional treatment plus levocarnitine for 14 days was associated with a higher composite response, lower myocardial-enzyme levels, higher LVEF and stroke volume, improved antioxidant indices, and a lower Th17/Treg ratio; no serious adverse events were reported.¹²² The single-center, short-duration design and surrogate outcomes leave the clinical and safety effects uncertain.

Overall, the human literature provides short-term adjunctive signals rather than confirmatory efficacy evidence. No intervention has been evaluated in an adequately powered multicenter trial with hard cardiovascular endpoints, long-term remodeling, recurrence, or mortality as a prespecified primary outcome. These preparations should therefore remain investigational adjuncts to guideline-based care.

Preclinical Pharmacology of Herbal Medicine-Based Interventions in Viral Myocarditis

Preclinical research on herbal medicine-based interventions for viral myocarditis has primarily been conducted using cell and animal models. These studies increasingly support the view that their therapeutic potential lies in the pharmacological regulation of immune-inflammatory injury during early viral replication and in the mitigation of myocardial remodeling during the subacute and chronic phases. Available evidence suggests a multi-target mode of action involving the suppression of NF-κB-associated inflammatory signaling, correction of Th17/Treg imbalance, reduction of cytokine cascades and cardiomyocyte injury, and modulation of oxidative stress, mitochondrial homeostasis, and the autophagy-lysosomal axis. Herbal medicine-based interventions may also regulate apoptosis and pyroptosis, thereby improving histopathological injury and cardiac function. More recent studies integrating omics analyses, network pharmacology, and functional validation have moved mechanistic research beyond single targets toward pathway networks and stage-specific regulatory mechanisms, underscoring the translational importance of disease stage, key signaling nodes, and intervention timing (Table 2 and Supplementary Table 2).

Table 2.

Representative Preclinical Studies of Herbal Medicine-Based Interventions for Viral Myocarditis

No.	Intervention	Experimental Model/Sample	Dosage	Treatment Duration	Phenotypic Outcomes	Mechanistic Outcomes
1	Buyang Huanwu Decoction155	In vivo: 144 BALB/c mice	6, 18, 36g/kg/d	30d	HW/BW↓, myocardial histopathology score↓	MMP-3↑, TIMP-1↑, type I/type III collagen ratio↓, MMP/TIMP imbalance↓, MMP-1↓, MMP-9↓
2	Jingfang Granules156	In vivo: 90 C57BL/6 mice	11.5, 23, 34.5g/kg	8w	Myocardial pathological histological score↓, myocardial cell apoptosis rate↓, and fibrosis area↓	Bcl-2↑, Beclin-1↑, LC3↑, Nvl↑, Khdc4↑, Mcoln1↑, SEC14l1↑, NF-κB↓, TNF-α↓, P-ERK1/2↓, ERK1/2↓, p38 MAPK↓, TLR3↓, TGF-β↓, Bax↓, caspase-3↓, p62↓
3	Shenqi Fuzheng Injection157	In vivo: 120 BALB/c mice	0.4, 0.9mL/d	30d	Myocardial apoptosis index ↓	Fas/FasL↓
4	Oxymatrine158–161	In vivo: 50 BALB/c mice, 60 BALB/c mice, 25 SD rats, 105 BALB/c mice	13, 26, 52mg/kg/d;0.025, 0.1mg/kg/d;6.25, 25mg/kg/d;3.125, 6.25, 12.5, 25mg/kg/d	2w;10d;2w;4w	LVEF↑, FS↑, Ratio of necrotic myocardial tissue area to total area↓, Ratio of macrophage infiltration to total area↓, Myocardial pathological histological score↓, LDH↓, CK-MB↓, CK↓, LVEDD↓, LVESD↓	SOD↑, GSH-Px↑, Bcl-2↑, ATP/AMP↑, Calmodulin↑, IFN-γ↓, CVB3 mRNA↓, IL-8↓, CRP↓, TNF-α↓, MDA↓, Bax↓, FFA↓, LAC↓, ColI↓, ColIII↓, GRP78↓, CHOP↓, MIF mRNA↓
5	Berberine162,163	In vivo: 40 BALB/c mice, 48 BALB/c mice	50, 100mg/kg/d;50, 100mg/kg/d	2w;1w	LVEF↑, LVFS↑, cTnT↓, CK-MB↓, AST↓, CK↓, LDH↓	TNF-α↓, IL-6↓, IL-1β↓, CCL2↓, CCL5↓, CXCL10↓, CVB3 mRNA↓, AKT↓, p38 ↓, TLR4↓, NF-κB↓, CD68+↓
6	Icariin164,165	In vivo: 65 BALB/c mice, 50 BALB/c mice	80, 160mg/kg/d;60/90/120/150mg/kg/d	60d;10d	LVFS↑, Myocardial pathological histology score↓, CK↓, CK-MB↓, LDH↓, LVESD↓, LVEDD↓, CVF↓	CD8+↑, Treg↑, TNF-α↓, IL-1β↓, CXCL2↓, S100A6↓, β-catenin↓, c-Myc↓, caspase-3↓, PARP↓, PICP↓, PIIINP↓, TGF-β1↓, p-mTOR↓, p-p70S6K↓, p-4EBP1↓, CD4+↓
7	Baicalin/wogonoside166,167	In vivo: 60 BALB/c mice, 40 BALB/c mice	20, 50, 100mg/kg/d;50mg/kg/d	10d;1w	LVESD↑, LVEF↑, Myocardial cell apoptosis rate↓, LVIDd↓, NT-proBNP↓	Mitochondrial membrane potential in cardiomyocytes↑, IL-1β↓, IL-6↓, AKT↓, NF-κB↓, Cyt C↓, caspase-9↓, caspase-3↓
8	Tanshinone IIA168,169	In vivo: 75 BALB/c mice, 45 BALB/c mice	2.5, 5.0mg/mL/d;20mg/kg/d	2w;2w	SBP↑, DBP↑, LVEF↑, HW/BW↓, LDH↓, CK↓, CK-MB↓, cTnI↓, HR↓, LVESD↓, LVEDD↓, Myocardial pathological histological score↓	IL-4↑, IL-10↑, IFN-γ↓, IL-2↓, TNF-α↓, IL-6↓, IL-1β↓, TLR4↓, NF-κB↓, Improved Th1/Th2 balance
9	Astragaloside IV133,170,171	In vivo: 60 BALB/c mice, 30 C57BL/6 mice, 60 C57BL/6 mice	20, 40mg/kg/d;200, 300, 400mg/kg/d;100mg/kg/d	1w;1w;2w	LVEF↑, LVFS↑, myocardial fibrosis area↓, apoptosis rate↓, cTnI↓, LDH↓, CK-MB↓, LVPWd↓, E/E′↓	A20↑, NLRP3↓, IRF7↓, IFN-γ↓, IL-6↓, TNF-α↓, MCP-1↓, IL-1β↓, IL-18↓, caspase-1↓, caspase-8↓, caspase-3↓, FAS↓, FASL↓, p-IKKβ↓, p-IκBα↓, p-p65 ↓, NF-κB↓, NETs↓
10	Astragalus polysaccharide172	In vivo: 60 C57BL/6 mice	200mg/kg/d	2w	LVEF↑, FS↑, AST↓, LDH↓, CK-MB↓	IL-1β↓, IL-6↓, TNF-α↓, IFN-γ↓, MCP-1↓, TLR4↓, p-NF-κB p65↓

Notes: ↑, increased or upregulated; ↓, decreased or downregulated; +, positive or increased according to the original study; ~, range; in vivo, animal experiments; in vitro, cell-based experiments. Detailed preclinical evidence is provided in Supplementary Table 2.

TCM Compound Formula

Buyang Huanwu Decoction, first recorded in Medical Research Corrections, primarily emphasizes tonifying qi and promoting blood circulation. The potential value of VMC appears to lie mainly in the later repair stage, where it may target microcirculatory disturbances and remodeling associated with qi deficiency and blood stasis.^173,174 Animal studies have suggested that this formula can attenuate CVB3-induced myocardial fibrosis, as reflected by reduced collagen deposition and regulation of matrix metabolism, including downregulation of MMP-1 and MMP-9, upregulation of TIMP-1, rebalancing of the MMP/TIMP axis, and improvement in type I/III collagen-related indices and pathological scores.¹⁵⁵ These findings indicate that it may alleviate inflammation and remodeling by inhibiting abnormal ECM deposition and correcting the disordered matrix degradation. At the component level, astragaloside, ferulic acid, ligustrazine, and peucedanin may collectively contribute to anti-inflammatory, antioxidant, and microcirculation-improving effects, supporting its multi-pathway cardioprotective and anti-remodeling actions.¹⁷⁵

Danggui Buxue Decoction (DGBXD), derived from Li Dongyuan’s Analysis of Internal and External Diseases, consists of Astragalus and Danggui in a 5:1 ratio and is a representative formula for tonifying qi and generating blood. The potential mechanism of VMC may be summarized as strengthening the body to promote repair, mainly through immune and energy metabolism support, attenuation of inflammation and oxidative stress, and improvement of hemorheology and microcirculation to optimize the reparative microenvironment. Component studies have indicated that DGBXD contains saponins, flavonoids, polysaccharides, and organic acids, providing a material basis for its anti-inflammatory, antioxidant, and circulation-promoting effects.^176,177 From the perspective of the gut–heart axis, CVB3 infection may induce intestinal dysbiosis and metabolic disturbances associated with prolonged inflammation.¹⁷⁸ DGBXD has been reported to strengthen the intestinal mucosal barrier and regulate gut microbiota and mucosal immunity, thereby potentially reducing the systemic inflammatory burden and indirectly alleviating immune-mediated myocardial injury.¹⁷⁹ Animal studies have shown that DGBXD can reduce LDH, AST, and CK-MB levels while upregulating myocardial VEGF expression, suggesting myocardial protection through reduced cellular injury and the promotion of reparative angiogenesis and perfusion improvement.¹⁸⁰ DGBXD may be considered a multi-target candidate formula centered on replenishing qi, improving perfusion and the repair microenvironment, and possibly modulating systemic inflammation through gut immune–microbiota interactions.

Chinese Patent Medicine

Jingfang Granules (JFG) are derived from Jingfang Baidu San and follow the principles of dispelling wind, resolving exterior symptoms, clearing heat, and detoxifying. They are mainly used for viral myocarditis of the type where “external pathogenic factors invade the heart and the body’s vital energy is insufficient.” The formula consists of 11 herbs, including Cimicifuga, Fangfeng, and Qianghuo, aiming to expel pathogenic factors externally and regulate the meridians internally. In the CVB3-induced myocarditis model, continuous intervention for 8 weeks alleviated myocardial histological damage, inhibited the activation of NF-κB-related inflammatory signaling, and downregulated the expression of TNF-α, TLR3, and TGF-β molecules. Mechanistic studies suggest that JFG can upregulate the lysosomal channel MCOLN1, improve autophagy flux related to lysosomes, enhance autophagy mediated by Beclin1/LC3 and mitochondrial autophagy, promote the clearance of damaged mitochondria and excessive ROS, and stabilize mitochondrial function, thereby inhibiting mitochondrial pathway apoptosis (with increased Bcl-2 and decreased Bax and caspase-3).¹⁵⁶ Additionally, network pharmacology combined with in vitro and in vivo validations suggests that flavonoids, such as quercetin, luteolin, and kaempferol, can synergistically regulate the TNF-α/NF-κB pathway and reduce myocardial cell apoptosis, supporting its comprehensive protective effect against VMC inflammation.¹⁸¹

Sanqi Danshen Tablets are a combination of Panax notoginseng and Salvia miltiorrhiza, belonging to the category of promoting blood circulation and resolving stasis, and have been used for the prevention and treatment of cardiovascular diseases for a long time, with pharmacological effects such as antithrombotic, anti-inflammatory, and endothelial protection.¹⁸² Component and mechanism studies suggest that Panax notoginseng saponins can activate the CSE/H2S pathway to inhibit inflammation and reduce viral mRNA levels, thereby alleviating CVB3-induced myocardial edema and inflammatory infiltration.¹⁸³ Tanshinone IIA in the CVB3 model can reduce LDH and CK levels, improve hemodynamic and pump function, and increase survival benefits by inhibiting inflammation and regulating Th1/Th2 cytokine profiles (IFN-γ and IL-2 decrease, and IL-4 and IL-10 increase).¹⁶⁸ Consistent with individual evidence, animal studies suggest that Sanqi Danshen Tablets can reduce mortality, improve cardiac function, and downregulate damage indicators in the CVB3-related VMC model, while promoting the re-balance of Th17/Treg and CD4+/CD8⁺, demonstrating a multi-target intervention feature centered on immune re-calibration.¹⁸⁴

Wusen Erlian Granules target the “fundamental deficiency and superficial manifestation” of viral myocarditis, with the core being to benefit qi, nourish yin, and consolidate the foundation, while also clearing heat and detoxifying, promoting blood circulation, and regulating the meridians to protect the heart. The formula emphasizes the use of ginseng to strengthen the body and promote circulation, supplemented by Danshen to improve myocardial microcirculation, combined with Huanglian and Liuhua to inhibit inflammatory damage caused by toxic heat, and Shenqu and Kansui to regulate yin heat and immune response, supplemented by jujube seed and pericarp seed to calm the mind and relieve palpitations to improve related symptoms. The CVB3 model suggests that it can reduce CK isoenzymes and myocardial injury indicators, such as troponin and myoglobin, while increasing the indices of the spleen and thymus and the activity of NK cells, indicating that it may achieve comprehensive myocardial protection by reducing myocardial damage and optimizing antiviral immunity.¹⁸⁵

TCM Injection

Shenqi Fuzheng Injection focuses on nourishing the body’s vital energy and regulating inflammatory responses. It is suitable for the pathological process of “deficiency of vital energy as the root cause and damage by inflammation as the manifestation” in viral myocarditis.¹⁵⁷ It mainly originates from the extracts of Astragalus and Dangshen, emphasizing the enhancement of the body’s antiviral immune efficiency and correction of immune hyporesponsiveness. Current evidence suggests that it can promote interferon-related immune responses and enhance NK cell function.¹⁸⁶ In CVB3-related experimental models, Shenqi Fuzheng Injection improved the myocardial injury phenotype, reduced enzymatic indicators such as CK and CK-MB, and inhibited the Fas/FasL-mediated cell apoptosis process, demonstrating its synergistic anti-inflammatory and anti-apoptotic effects driven by immune balance, achieving myocardial protection, and disease course intervention.¹⁵⁷

TCM Monomers

Alkaloid

Dihydrolycorine (DL) is a lycorine-type alkaloid derivative found in Lycoris plants. The bulb of the Lycoris genus is commonly used in traditional medicine for “anti-inflammatory, detoxification, swelling reduction, and pain relief,” The alkaloids of the Lycoris family also have broad-spectrum biological activities (including antiviral and anti-inflammatory potential), providing a natural productological basis for its repositioning in infection-related myocardial injury. Recent animal studies have suggested that DL has clear organ protection and mechanism-targeting characteristics against CVB3-induced viral myocarditis (VMC). Bai et al¹⁸⁷ evaluated serum Mb, CK-MB, cTnI, and hemodynamic indicators (LVP, ±dp/dtmax) in VMC rats and found that 7 days of treatment reduced myocardial injury markers, improved cardiac function, and alleviated inflammation and apoptosis. At the same time, it downregulated endoplasmic reticulum stress (ERS)-related CHOP, GRP78/GRP94, and Bax, and upregulated Bcl-2, suggesting that its key action axis is to inhibit ERS-mediated apoptosis.¹⁸⁷ Yang et al further conducted causal verification using the ERS agonist tunicamycin. Tunicamycin could partially reverse the improvements of DL on GRP78/CHOP, dp/dtmax, LVEF, CK-MB, and TUNEL apoptosis index; in addition, DL could downregulate IL-1β mRNA, suggesting its effect is related to ERS dependence and inflammatory cascade inhibition.¹⁸⁸

Oxymatrine (OMT) is a quinolizidine-type alkaloid derived from plants, such as Sophora flavescens, with anti-inflammatory, immunomodulatory, and antiviral multi-target activities. In the CVB3-induced myocarditis model, Jiang et al reported that OMT could inhibit viral replication, reduce myocardial virus titer, alleviate inflammatory pathological damage, and downregulate TNF-α, suggesting that it can simultaneously inhibit viral load and inflammatory response.¹⁵⁸ Further studies have shown that OMT downregulates MIF-related pro-inflammatory recruitment signals and reduces myocardial necrosis and inflammatory infiltration, thereby reducing the local inflammatory load.¹⁵⁹ During the disease progression and remodeling stage, OMT is related to mitochondrial protection and energy metabolism regulation, inhibits ERS-related apoptosis signals (GRP78, CHOP) and fibrosis deposition (periostein, I/III type collagen), improves LVEDD, LVEF, and FS, and reduces apoptosis and viral load, suggesting that it may alleviate adverse remodeling.¹⁶⁰ Additionally, OMT reduces inflammatory and oxidative stress indicators (IL-8, CRP, TNF-α, and MDA); regulates Bcl-2/Bax-related mitochondrial apoptosis pathways; reduces LDH, CK-MB, and CK levels; and improves LVEF, thereby alleviating structural and functional damage.¹⁶¹ In vitro studies have also shown that OMT inhibits Smad-2/3/4 activation, reduces fibroblast proliferation and myofibroblast differentiation, and reduces I/III collagen secretion and hydroxyproline levels, suggesting that it may inhibit ECM deposition and delay remodeling through the TGF-β1/Smad pathway.¹⁸⁹

Berberine (BBR) is a natural isoquinoline alkaloid that is mainly found in medicinal plants such as Coptis chinensis and Berberis vulgaris. Traditionally, it is used for clearing heat and drying dampness, purging fire, and detoxifying. Modern pharmacological research has shown that it has anti-infective, anti-inflammatory, antioxidant, and anti-fibrotic activities, providing a basis for research on viral myocarditis (VMC).¹⁴² In the CVB3 myocarditis model, Dai et al administered BALB/c mice a continuous 7-day intragastric administration starting 1 d before infection and observed that BBR increased the survival rate and improved cardiac function (EF, FS), reduced cardiac damage and viral load (myocardial CVB3 particles, vp1 mRNA, and virus titer), and downregulated inflammatory factors/cytokines such as TNF-α, IL-6, IL-1β, CCL2, CCL5, and CXCL10, while reducing CD68 + macrophage infiltration, suggesting that it can simultaneously inhibit viral replication and the inflammatory cascade.¹⁶² In vitro studies have also shown that BBR decreases VP1 expression and viral titer, and inhibits JNK and p38 MAPK phosphorylation, suggesting that JNK/p38-MAPK is involved in its anti-CVB3 effect.¹⁶³ Derivatives based on BBR have been reported to have stronger inhibition of CVB1-6, and by inhibiting ERK, JNK, and p38-MAPK activation, they downregulate VP1 protein and RNA expression, supporting the host MAPK signaling and viral replication coupling pathway as potential intervention targets.¹⁹⁰

Flavonoid Glycosides

Icariin (ICA), a major prenylated flavonoid glycoside from Epimedium species, has been shown to possess anti-inflammatory, antioxidant, and immunomodulatory activities, with the potential to interfere with viral replication, inflammatory cascades, and cardiomyocyte injury in VMC.¹⁹¹ In CVB3-related models, ICA reduced the viral load in HeLa, H9C2, and neonatal rat ventricular myocytes at 1 and 10 μM, and short-term administration (3 days) alleviated myocardial injury in intraperitoneally infected BALB/c mice. Mechanistically, ICA inhibited the S100A6/β-catenin/c-Myc pathway; reduced apoptosis; downregulated TNF-α, IL-1β, and CXCL2; and modulated splenic CD4+ T, CD8+ T, and Treg cell proportions, indicating both antiviral and immune-inflammatory regulatory effects. It also shows inhibitory activity against EV71, CVA6, and CVA16.¹⁶⁴ Additional animal studies found that ICA downregulated mTOR-p70S6K/4EBP1 signaling, reduced fibrosis, and improved cardiac function, suggesting a potential benefit in later-stage remodeling of the VMC.¹⁶⁵

Baicalin (Bai), a representative flavonoid glycoside isolated from the dried roots of Scutellaria baicalensis, has also shown protective effects against CVB3-related myocarditis.¹⁹² Studies have suggested that it limits viral replication and myocardial inflammation by downregulating lipid synthesis-related molecules, reducing cellular lipid load, and decreasing LC3-II-associated autophagosome formation.^193,194 In vivo, baicalin can be converted to baicalein, which inhibits both viral 2A protease activity and caspase-1 during early CVB3 infection, thereby balancing viral protein processing and reducing inflammasome activation, ultimately alleviating myocardial inflammation and tissue injury.¹⁹⁵ Oral baicalin also inhibits cardiomyocyte apoptosis in VMC mice, improves ventricular remodeling, and attenuates heart failure phenotypes, with mechanisms linked to the mitochondrial apoptotic pathway.¹⁶⁶ Another Scutellaria flavonoid glycoside, wogonoside, likewise inhibited AKT/NF-κB activation and reduced IL-1β and IL-6 levels, suggesting that the PI3K/AKT–NF-κB axis may represent a shared anti-inflammatory node among baicalin-related compounds.¹⁶⁷ Further evidence indicates that baicalin can regulate JAK/STAT, TLR, and NF-κB signaling, influencing IFN-related effectors and apoptosis/inflammation-related mediators, thereby limiting viral proliferation while reducing secondary immune-inflammatory myocardial injury.¹⁹⁶

Coumarin

Osthole (Ost) is a natural coumarin found mainly in Cnidium monnieri fruit and other Apiaceae medicinal plants.¹⁹⁷ Pharmacological studies suggest that it mainly exerts its effects by regulating immune inflammation, and that the key pathways involve the PI3K/Akt and NF-κB inflammatory transcription axes.¹⁹⁸ In the viral myocarditis model induced by CVB3, Ost inhibited the activation of Akt/NF-κB and reduced the levels of pro-inflammatory factors while downregulating the viral RNA load in the myocardium. This suggests that it may limit viral replication-supporting conditions and alleviate myocardial damage by weakening the inflammatory microenvironment.¹⁹⁹ Considering the promoting effects of inflammasomes and mtDNA-STING-related signals on the persistence of inflammation and tissue damage during the course of VMC, targeting of the NF-κB axis by Ost has certain mechanistic rationality.²⁰⁰

Terpenoids

Morroniside (Mor), an iridoid glycoside derived mainly from the fruit pulp of Cornus officinalis, is a representative active constituent. Cornus officinalis was first recorded in Shennong’s Herbal Classic and is described in modern pharmacopoeias as nourishing the liver and kidneys and exerting astringent effects.²⁰¹ In CVB3-induced myocarditis models, Mor improved cardiac function and attenuated myocardial injury. Mechanistically, it appears to inhibit NLRP3 inflammasome activation, reduce IL-1β and IL-18 signaling, correct mitochondrial apoptosis imbalance, and downregulate caspase-3 activation, thereby limiting cardiomyocyte loss at both inflammatory amplification and apoptosis.²⁰² Mor has also been shown to promote cell cycle-related programs and attenuate fibrotic remodeling during myocardial repair.²⁰³

Tanshinone IIA (Tan IIA), a lipophilic diterpene quinone isolated from Salvia miltiorrhiza, possesses antioxidant and immunoregulatory properties. Its effects are mainly linked to the TLR/MAPK–NF-κB and Nrf2 pathways, thereby suppressing inflammatory transcription and oxidative stress.²⁰⁴ In CVB3 models, Tan IIA improved myocardial injury and cardiac function, reduced enzyme markers of necrosis, downregulated Th1-related cytokines, such as IFN-γ and IL-2, and increased IL-4 and IL-10, indicating a role in restoring immune homeostasis.¹⁶⁹ It also decreases the expression of the endoplasmic reticulum stress markers GRP78 and L-type calcium channels, suggesting additional effects on calcium homeostasis and stress injury.²⁰⁵

Andrographolide (Andro), the major diterpene lactone isolated from the aerial parts of Andrographis paniculata, has traditionally been used to clear heat, detoxify, and reduce inflammation.²⁰⁶ Modern studies support its anti-infective potential, particularly through suppression of host inflammatory networks.²⁰⁷ In CVB3-induced myocarditis, Andro improves cardiac function, reduces myocardial injury, lowers inflammatory and damage markers, and increases IL-10 while activating anti-inflammatory STAT3 signaling, suggesting cardioprotection through the enhancement of endogenous anti-inflammatory responses.²⁰⁸ Related preparations have also been reported to downregulate ST2 and ameliorate post-inflammatory fibrosis, indicating possible anti-remodeling effects.²⁰⁹

Astragaloside IV (AS-IV), a representative tetracyclic triterpenoid saponin from Astragalus membranaceus, is a commonly used pharmacological quality marker.²¹⁰ The effects of CVB3-induced VMC mainly involve immunomodulation and myocardial protection, with additional antiviral and anti-remodeling potential.²¹¹ Mechanistically, AS-IV upregulates A20, inhibits NF-κB activation, and reduces inflammatory cell infiltration and pro-inflammatory mediator release, thereby attenuating histological injury and improving cardiac function.¹³³ Some studies have further suggested that AS-IV reduces CVB3 replication and enhances IFN-γ-related antiviral responses, indicating that it may suppress immune-mediated injury without compromising antiviral defense.²¹² At the cell fate level, AS-IV inhibits the Fas/FasL–caspase-8/3 extrinsic apoptotic pathway, reduces cardiomyocyte loss, and helps alleviate chronic fibrotic progression.¹⁷⁰ More recent evidence also implicates the IRF7/NLRP3 axis, suggesting that AS-IV may inhibit inflammasome-related responses and limit NET formation, thereby reducing the risk of persistent inflammation and fibrotic remodeling.¹⁷¹

Lignans

Manassantin B (Man B) is a lignan isolated from Saururus chinensis.²¹³ Current evidence suggests that it primarily modulates host antiviral responses. During early infection, Man B inhibits CVB3 RNA replication and VP1 expression while inducing mitochondrial stress, including increased mitochondrial ROS and cytosolic mtDNA release. These changes activate the cGAS-STING-TBK1-IRF3 pathway and enhance type I interferon-related transcription, thereby limiting viral amplification.²¹⁴ Because mtDNA-STING signaling also contributes to cardiomyocyte-macrophage inflammatory crosstalk, this pathway may have both antiviral and immunomodulatory effects.⁸¹ Overall, Man B may protect the myocardium by restricting viral replication and modulating inflammatory signaling.

Polyphenols

Curcumin (Cur) is a representative diarylheptanoid polyphenol found in the rhizomes of turmeric. It is one of the core substances underlying its pharmacological activity.²¹⁵ Animal experiments have shown that Cur can alleviate myocardial inflammatory necrosis and improve outcomes by reducing the levels of pro-inflammatory cytokines and markers of myocardial injury. At the molecular level, it mainly inhibits NF-κB and is accompanied by the downregulation of iNOS and the attenuation of caspase-3-mediated apoptosis, suggesting that it reduces pathological immune damage by inhibiting inflammatory transcription and limiting apoptosis.²¹⁶ Further cell research indicated that this effect is related to miR-21 regulation. Cur downregulates miR-21 and inhibits key phosphorylation events of NF-κB, thereby reducing the expression of inflammatory factors and apoptosis.²¹⁷ Additionally, Cur intervention in the ubiquitin-proteasome system can inhibit the expression of RNA/protein related to CVB3 replication and reduce the viral titer, suggesting that in addition to immune regulation, it also has a host-dependent antiviral action site.²¹⁸

Anthraquinones

Emodin (Emo) is a natural anthraquinone derivative that is mainly found in medicinal herbs, such as rhubarb, Polygonum cuspidatum, and Rehmannia glutinosa.²¹⁹ Current studies suggest that emodin has both antiviral and anti-inflammatory properties in CVB3-related viral myocarditis: at the antiviral level, emodin intervenes in the Akt/mTOR axis and its downstream translation regulation, reducing the translation efficiency of viral proteins, thereby limiting the replication and amplification of CVB3;^220,221 at the anti-inflammatory and myocardial protection level, it downregulates TLR4-related stress and inhibits p38 MAPK and NF-κB signaling, weakening the inflammatory cascade and positive feedback of tissue damage after pathogen recognition, manifested as a decrease in viral load and reduction in inflammatory infiltration and necrosis.^220,221

Natural Small Molecules

Trehalose (Tre) is a nonreducing disaccharide studied as an autophagy modulator.²²² In a CVB3-induced mouse model, trehalose enhanced B-cell autophagic flux, with increased LC3-II and LAMP2 and decreased p62, and attenuated myocardial inflammatory injury. Lysosomal inhibition or blockade of AMPK/ULK1 weakened these effects, supporting an AMPK/ULK1-dependent mechanism.²²³ This evidence is limited to one preclinical study.

Macromolecular Components

Mongolian astragalus mainly comes from Astragalus mongholicus, and its medicinal part is the dried root. Among its complex components, total Astragalus saponins (TAS) and astragalus polysaccharide (APS) are the most representative.¹⁷² Current VMC studies suggest that the effects of astragalus-related components can be summarized as synergistic effects of anti-inflammation, anti-apoptosis, and anti-remodeling. TAS focuses on inhibiting death receptor pathways, such as TNF-α/Fas, reducing the apoptotic load of cardiac cells, thereby alleviating acute injury and improving outcomes.²²⁴ APS is more inclined to inhibit the innate immune inflammatory hub by downregulating TLR4/NF-κB and downstream inflammatory factors, weakening the inflammatory cascade, and protecting against subsequent expansion and fibrotic remodeling.¹⁷²

Discussion

Mechanistic Convergence Between Immune-Inflammatory Injury and Herbal Medicine-Based Interventions

VMC shows marked clinical heterogeneity, ranging from self-limiting illness to DCM, malignant arrhythmias, acute heart failure, and sudden death. Because broadly effective cause-specific therapies are unavailable, management remains centered on supportive care and complication control. Long-term outcome is shaped by the magnitude and timing of inflammation, cardiomyocyte death, and myocardial remodeling. Herbal medicine-based interventions have therefore been investigated as adjunctive strategies whose multicomponent and multitarget actions may align with the complex pathobiology of VMC. Systematic reviews and meta-analyses suggest possible improvements in symptoms, electrocardiographic recovery, and selected functional and biochemical measures when these interventions are added to conventional therapy. However, confidence in these findings is limited by small samples, inadequate blinding, and heterogeneous endpoints.²²⁵

The principal mechanistic convergence involves modulation of immune-inflammatory injury. During the acute phase, innate immune activation, cardiomyocyte damage, and viral induction of TLR-related, NF-κB, and NLRP3 signaling are central drivers of tissue injury. Experimental studies suggest that herbal formulas, injectable preparations, and bioactive compounds may suppress inflammatory transcription and cytokine amplification, reduce oxidative and mitochondrial injury, and modulate apoptosis, pyroptosis, autophagy, and subsequent fibrosis.²²⁶ This network-level activity may explain why reported effects span myocardial injury biomarkers, inflammatory mediators, cardiac function, and structural remodeling rather than a single pathway.

At the same time, these findings also highlight the importance of disease stage and biological context. The dominant mechanisms of early viral replication differ from those in the subacute and chronic phases, where maladaptive immune activation, persistent low-grade inflammation, extracellular matrix remodeling, and ventricular dysfunction become more prominent. Therefore, the therapeutic relevance of herbal medicine-based interventions is likely to depend not only on the pharmacological profile of the intervention itself but also on timing, immune phenotype, and complication risk. This provides a strong rationale for a stage-based and mechanism-informed framework for interpreting current evidence and designing future studies. Figure 7 maps the principal therapeutic targets and representative interventions across the disease course and presents a bench-to-bedside translational roadmap. Table 3 provides an integrated comparison of the principal molecular targets, experimental models, reported findings, available human clinical evidence, and key limitations of the reviewed interventions.

Figure 7.

Disease stage-specific therapeutic targets and a bench-to-bedside translational roadmap for natural products and herbal medicines in viral myocarditis.

Table 3.

Comprehensive Evidence Summary of Natural Product- and Herbal Medicine-Based Interventions in Viral Myocarditis: Molecular Targets/Pathways, Experimental Models, Clinical Evidence, Certainty, and Limitations

Intervention	Clinical Evidence: Studies, Participants, and Design	Experimental Model(s)	Molecular Targets/Pathways	Key Outcome Domains	Overall Risk of Bias	GRADE Certainty by Outcome	Limitations and Interpretation
Zhigancao Decoction106–108	3 (n=222); Three short-term randomized trials	—	NF-κB-associated inflammation; oxidative stress (SOD/MDA); apoptosis; myocardial injury	Symptoms/composite response; ECG; myocardial injury and cardiac stress markers; inflammatory/oxidative markers	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Repeated reports, but small single-center trials and no long-term clinical outcomes.
Shuxin Tongmai Decoction109–111	3 (n=372); Three randomized trials	—	Inflammatory cytokines; oxidative stress; Beclin-1/LC3 autophagy; Bcl-2/caspase-3 apoptosis	Composite/ECG response; myocardial injury markers; CMR-derived ventricular function; inflammatory, oxidative and autophagy-related markers	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Largest aggregate sample among the included formulas, but trials were open label.
Yiqi Jiedu Decoction126,127	2 (n=164); Two randomized trials	—	Th1/Th2 cytokine balance (IFN-γ/IL-4); IL-6/IL-8; myocardial injury and contractile function	Composite response; TCM symptoms; myocardial enzymes; SV/LVEF/CO; cytokines	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Preliminary supportive evidence only.
Guizhi Longgu Muli Decoction132	1 (n=60); One nonrandomized controlled study	—	CVB3 load; NF-κB; TNF-α/IL-6/IL-2; inflammatory signaling and myocardial injury	TCM symptoms; ECG response; myocardial enzymes; inflammatory cytokines	High risk	All reported outcomes: very low	Insufficient evidence because allocation was nonrandom and only surrogate outcomes were assessed.
Shenfu Yangrong Decoction138	1 (n=100); One randomized trial	—	TLR/NF-κB; IL-17/IL-27; oxidative stress; apoptosis and myocardial injury	Composite response; TCM symptoms; cTnI/H-FABP; inflammatory markers	Some concerns	Clinical response: very low; biomarkers: low; safety: very low	Single-center evidence requiring independent replication.
Shengmai Xianxiong Decoction143	1 (n=60); One randomized trial	—	Viral replication; NF-κB/MAPK; oxidative stress; T-cell subsets and myocardial injury	Composite response; cTnI; T-cell subsets	Some concerns	Clinical response: very low; biomarkers: low	Single small trial; clinical significance remains uncertain.
Huangqi Granules112–116	5 (n=377); Four randomized trials and one nonrandomized study	—	Th1/Th2 and Th17/Treg balance; NF-κB/NLRP3; miR-133/miR-155; inflammatory cytokines	Composite/ECG response; myocardial injury markers; SV/CO/LVEF; T-cell subsets, cytokines and miRNAs	Some concerns to high risk	Clinical response: very low; biomarkers/function: low; safety: very low	Broadest clinical evidence base among the included preparations, but populations, doses, and co-interventions were heterogeneous.
Wenxin Granules147,149	2 (n=159); Two randomized trials	—	HMGB1/IL-37; oxidative stress; apoptosis; endothelial and electrophysiological regulation	Composite/ECG response; Tei indices; CK-MB/cTnT; oxidative and inflammatory markers	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Limited to two short-term studies.
Qidong Yixin Oral Liquid117–120	4 (n=334); Four randomized trials	—	T-cell subsets; TNF-α/IL-6/IL-18; myocardial injury and ventricular function	Composite/ECG response; cardiac function; myocardial injury markers; immune and inflammatory markers	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Relatively broader evidence base, but outcome definitions and co-interventions were heterogeneous.
Huangqi Oral Liquid152	1 (n=68); One randomized placebo-controlled study	—	Treg/Th17; miR-146b/miR-155; RORγt/FoxP3; caspase-3 and cytotoxicity markers	Arrhythmias/ECG recovery; symptom duration/hospital stay; cardiac function; myocardial injury and Treg/Th17 markers	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Promising mechanistic signal based on one small trial.
Breviscapine Injection121	1 (n=82); One nonrandomized controlled study	—	SOD/GST antioxidant defense; NO; TNF-α/IL-6; myocardial enzyme release	Composite response; myocardial injury, inflammatory and oxidative markers; adverse events	High risk	All reported outcomes: very low	Evidence is insufficient and vulnerable to selection bias.
Xiangdan Injection122	1 (n=80); One randomized trial	—	Th17/Treg balance; SOD/GSH/MDA; immunoglobulins; myocardial injury and cardiac function	Composite response; symptom recovery; myocardial injury and cardiac function; oxidative/immune markers; adverse events	Some concerns	Clinical response: very low; biomarkers/function: low; safety: very low	Single short-duration study.
Buyang Huanwu Decoction155	—	144 BALB/c mice	MMP/TIMP balance; type I/III collagen; extracellular-matrix remodeling	Histopathology and HW/BW; collagen and matrix-remodeling markers	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single mouse study; high experimental doses; no human VMC evidence.
Danggui Buxue Decoction180	—	60 BALB/c mice	VEGF; myocardial injury and reparative angiogenesis	LDH, AST, CK-MB and myocardial VEGF	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single study with surrogate endpoints; no replication or human VMC evidence.
Jingfang Granules156,181	—	C57BL/6 mice and in vitro validation	MCOLN1/lysosomal autophagy; Beclin-1/LC3; NF-κB; ERK/p38 MAPK; TLR3; TGF-β	Histopathology, apoptosis and fibrosis; autophagy, inflammation and mitochondrial quality control	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Complex multicomponent formulation; evidence derives mainly from one animal program; composition and dose translation remain uncertain.
Sanqi Danshen Tablets184	—	90 BALB/c mice	FoxP3/SENP2; Th17/Treg; TLR4/Notch1; MIF	LVEF, heart rate and myocardial injury markers; immune-cell balance	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single mouse study; limited independent replication; no human VMC trial.
Wusen Erlian Granules185	—	60 BALB/c mice	NK-cell activity and immune regulation	Myoglobin, cTnI and CK; NK-cell activity	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single short-duration animal study with limited mechanistic resolution.
Shenqi Fuzheng Injection157	—	120 BALB/c mice	Fas/FasL-mediated apoptosis	Cardiomyocyte apoptosis index	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single mouse study; injectable product standardization and clinical safety require confirmation.
Dihydrolycorine187,188	—	SD rats and BALB/c mice	Endoplasmic reticulum stress markers (GRP78, GRP94, and CHOP); Bcl-2/Bax; caspase-3/12; inflammatory cytokines	LVEF/LVFS, histopathology, apoptosis and myocardial injury markers	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Rodent-only evidence; limited pharmacokinetic, dose optimization, and safety data.
Oxymatrine158–161,189	—	BALB/c mice, SD rats, and cultured rat cardiac fibroblasts	Viral replication; MIF; TNF-α/IL-8/CRP; oxidative stress; Bcl-2/Bax; ER stress; TGF-β/Smad	Viral load, inflammation, cardiac function, apoptosis and fibrosis/remodeling	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Repeated preclinical evidence, but models and doses were heterogeneous; no human VMC efficacy trial.
Berberine162,163,190	—	BALB/c mice and CVB3-infected cell models	CVB3 replication; JNK/p38 MAPK; TLR4/NF-κB; chemokines and macrophage recruitment	Survival and cardiac function; viral load; myocardial enzymes; inflammatory infiltration	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	No human VMC evidence; low oral bioavailability and formulation-dependent exposure limit translation.
Icariin164,165	—	BALB/c mice	S100A6/β-catenin/c-Myc; mTOR-p70S6K/4EBP1; inflammatory cytokines; apoptosis/fibrosis	Cardiac function, histopathology, fibrosis, and myocardial injury markers	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Animal-only evidence; long treatment courses and high doses reduce direct clinical comparability.
Baicalin166,193,195	—	BALB/c mice and cardiomyocyte studies	Cellular lipid synthesis/viral replication; AKT/NF-κB; mitochondrial Cyt c/caspase-9 apoptosis	LVEF, ventricular dimensions, NT-proBNP and apoptosis	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Limited replication and variable functional outcomes; oral bioavailability remains a translational barrier.
Osthole199	—	30 BALB/c mice	PI3K/Akt/NF-κB; IL-1β and TNF-α	Inflammatory molecular endpoints; no cardiac functional outcome reported	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single small animal study; no cardiac-function endpoint or human evidence.
Morroniside202	—	36 SD rats	NLRP3/ASC/caspase-1 inflammasome; IL-1β/IL-18; Bcl-2/Bax/caspase-3	Myocardial injury markers and apoptosis/pyroptosis signaling	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single rodent study; no independent replication, pharmacokinetic characterization, or human VMC data.
Tanshinone IIA168,169	—	BALB/c mice	TLR4/NF-κB; Nrf2; Th1/Th2 balance; inflammatory cytokines	Hemodynamics, LVEF, ventricular dimensions, enzymes, histopathology and cytokines	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Preclinical-only VMC evidence; formulation, solubility and exposure variability require standardization.
Andrographolide208	—	30 BALB/c mice	IL-10/STAT3; PI3K/Akt/NF-κB	Hemodynamics, ventricular structure and cTnI; inflammatory signaling	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single mouse study; broad pathway claims require replication and target engagement confirmation.
Astragaloside IV133,170,171,212	—	BALB/c and C57BL/6 mice	A20/TNFAIP3; IRF7/NLRP3; NET formation; caspase-dependent apoptosis; antiviral IFN-γ	LVEF/LVFS, fibrosis, apoptosis, myocardial injury and inflammatory/NET endpoints	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Relatively repeated animal evidence, but wide dose range, no human VMC trial and uncertain exposure-response relation.
Manassantin B214	—	CVB3-infected Vero cells and systemic CVB3-infected BALB/c mice	STING/TBK1/IRF3; mitochondrial ROS and cytochrome c; antiviral cytokine signaling	Viral RNA and inflammatory mediators; innate antiviral signaling	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Non-cardiac cell and systemic infection models; no cardiac-specific functional endpoint, pharmacokinetic characterization, or human VMC evidence.
Curcumin216–218	—	BALB/c mice and H9c2 cardiomyocytes	NF-κB/IκB; miR-21; iNOS; MCP-1; caspase-3; ubiquitin-proteasome/viral replication	Apoptosis, myocardial enzymes, inflammation and viral replication	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	No human VMC evidence; poor bioavailability and formulation dependence remain major limitations.
Emodin220,221	—	BALB/c mice and CVB3-infected cell models	CVB3 protein translation and replication; TLR4/p38 MAPK/NF-κB; inflammatory cytokines	Histopathology, viral RNA and inflammatory signaling	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Animal/cell evidence only; safety, exposure and off-target effects need formal evaluation.
Trehalose223	—	48 C57BL/6 mice	AMPK/ULK1; LC3-II/LC3-I; LAMP2; p62; B-cell autophagy	Autophagic flux and myocardial injury	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single study focused on surrogate autophagy endpoints; no human VMC evidence.
Total Astragalus Saponins224	—	45 BALB/c mice	TNF-α; Fas/FasL; apoptosis and fibrosis	LVEF, apoptosis, cardiac weight, fibrosis and myocardial enzymes	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single mixture study; active component attribution and batch standardization remain uncertain.
Astragalus Polysaccharide172	—	60 C57BL/6 mice	TLR4/NF-κB p65; IL-1β/IL-6/TNF-α/IFN-γ/MCP-1	LVEF/FS, myocardial enzymes and inflammatory cytokines	Not applicable (no clinical study)	Not applicable (no human clinical evidence)	Single animal study; extract composition, molecular-weight distribution and clinical dose equivalence require clarification.

Notes: An em dash indicates that the corresponding clinical-evidence or experimental-model field is not applicable. Detailed risk-of-bias and qualitative GRADE-informed judgments are provided in Supplementary Tables 3 and 4.

Translational Relevance and Current Evidence Gaps

Despite encouraging signals, current evidence is insufficient to define the clinical role of herbal medicine-based interventions in VMC. Supportive care remains the therapeutic cornerstone, and specific antiviral or immune-targeted treatments have not shown consistent benefit across broad patient populations. Immunosuppression or immunomodulation is therefore used cautiously, generally after pathological classification and exclusion of persistent viral replication.^227,228 Within this context, herbal medicine-based interventions are most plausibly positioned as adjunctive rather than replacement therapies, particularly for patients with inflammatory activation, myocardial injury, or risk of adverse remodeling.

Several evidence gaps limit clinical translation. First, most studies emphasize surrogate outcomes, including symptom scores, electrocardiographic changes, myocardial enzymes, inflammatory biomarkers, and short-term echocardiographic indices, whereas hard clinical outcomes, long-term remodeling, recurrence, and major adverse cardiovascular events are rarely assessed. Second, inconsistent disease staging, diagnostic criteria, and endpoint definitions hinder identification of responsive subgroups and reliable estimation of treatment effects.²²⁹ Third, much of the preclinical evidence derives from CVB3 models, which cannot fully reproduce the heterogeneity of human VMC in viral etiology, immune phenotype, therapeutic window, or disease trajectory.

Several therapeutic mechanisms, particularly autophagy, are context-dependent and potentially bidirectional in VMC. Interventions targeting these pathways may therefore differ in benefit across disease phases, cell populations, and inflammatory states and require rigorous validation before clinical extrapolation.^230,231 Future studies should define the relevant disease stages, immune-inflammatory phenotypes, and complication-risk groups more precisely. Greater use of primary human cardiomyocytes, cardiac organoids, patient-derived samples, and well-characterized real-world cohorts may further narrow the gap between experimental findings and clinical application.

Pharmacokinetics, Bioavailability, Dose Optimization, Formulation Standardization, and Herb–Drug Interactions

Consistent exposure, formulation design, and quality standardization are additional barriers to translation. Many bioactive monomers have poor solubility, limited permeability, low oral bioavailability, and substantial interindividual variability in systemic exposure. For example, animal studies indicate that AS-IV has low oral bioavailability,²³² while its intestinal-microbial conversion to cycloastragenol suggests that both absorption and microbiota-dependent metabolism influence effective exposure.²³³ Unstable exposure can obscure pharmacological efficacy and complicate benefit-risk assessment. Formulation strategies such as cyclodextrin inclusion, injectable delivery, and nanodelivery may improve exposure or dose-exposure predictability for poorly soluble compounds.^234,235 Future studies should therefore complement nominal dosing with exposure-effect analyses using standardized, quality-consistent formulations.

Dose optimization remains particularly challenging because the doses used in animal studies vary substantially across compounds, formulations, administration routes, and treatment durations, and are rarely linked to plasma or myocardial exposure. Nominal doses expressed only as mg/kg therefore cannot be directly extrapolated to patients. Future studies should define exposure–response and exposure–toxicity relationships, establish pharmacokinetically justified human dose ranges, and determine whether changes in formulation or administration route alter the systemic exposure of active constituents and their metabolites.

Standardization is particularly important for complex herbal formulas. Variability in botanical identity, geographic origin, cultivation and harvesting conditions, processing, extraction, formulation, storage, and production scale can compromise batch consistency, dose comparability, and therapeutic reproducibility. Regulatory development should therefore include authenticated raw materials, good-manufacturing-practice-compliant production, validated extraction and formulation procedures, and predefined specifications for identity, purity, potency, stability, and batch-to-batch consistency. Quality-control packages should combine chromatographic or mass-spectrometric fingerprinting with quantitative multi-marker analysis, contaminant and adulterant testing, and, where feasible, mechanism-relevant biological activity assays. Harmonization of pharmacopoeial standards and regulatory classification across herbal medicines, botanical drugs, and dietary supplements will also be necessary to support multicenter trials and international clinical use.^60,236

Herb-drug interactions also require closer evaluation because herbal interventions are generally used with conventional antiviral or immunomodulatory agents, antiplatelet or anticoagulant therapy, antiarrhythmic drugs, and guideline-directed heart-failure treatment. Pharmacokinetic and pharmacodynamic interactions may alter systemic exposure, therapeutic response, or adverse-event risk through drug-metabolizing enzymes, membrane transporters, protein binding, or additive pharmacodynamic effects; however, formulation-specific evidence remains sparse. Future clinical studies should document concomitant therapies systematically and prospectively monitor hepatic and renal function, coagulation indices, cardiac rhythm, and treatment-emergent adverse events rather than infer interaction risk solely from isolated constituents. Such evaluation is necessary to define the boundaries of safe and rational combination therapy.

Safety Evaluation and Future Research Priorities

Safety remains insufficiently characterized. Adult VMC studies generally report infrequent adverse events and no clear excess over control groups, and many studies of injectable preparations report no serious events. However, monitoring and reporting are inconsistent, preventing reliable assessment of the full risk spectrum.²²⁶ Major concerns include hypersensitivity to injectable preparations and poor reproducibility of chemically complex formulas. Injectable products may induce pseudo-allergic reactions at first exposure through mechanisms distinct from classical IgE-mediated allergy, underscoring the need for stronger risk identification and early-warning systems.²³⁷ Shenmai injection has been associated with immediate adverse-reaction phenotypes, possibly through the p-i mechanism,²³⁸ while emerging evidence implicating MRGPRX2 supports pharmacovigilance frameworks that integrate product composition, receptor-level mechanisms, and individual susceptibility.²³⁹

Evidence beyond hypersensitivity is also limited. Most experimental studies lack systematic toxicological evaluation, and tolerability data for individual compounds such as AS-IV cannot substitute for standardized assessment of hepatic, renal, reproductive, genetic, or cardiac electrophysiological toxicity. Future studies should therefore adopt an integrated safety framework spanning preclinical toxicology, formulation-specific risk assessment, and real-world pharmacovigilance.

Precision medicine may improve therapeutic relevance because VMC is heterogeneous in viral etiology, disease stage, immune activation, myocardial injury, and progression toward fibrosis or ventricular dysfunction. Future studies should evaluate biologically defined subgroups characterized by viral persistence, excessive innate or adaptive immune activation, oxidative-mitochondrial injury, or established remodeling. Candidate stratification and response biomarkers include viral nucleic-acid or serological measures, cardiac troponins and natriuretic peptides, inflammatory cytokines and immune-cell phenotypes, cardiac magnetic resonance indices of edema and fibrosis, and transcriptomic, proteomic, or metabolomic signatures. These markers remain exploratory and require prospective validation. Biomarker-guided enrichment or adaptive trials should determine whether they can identify responsive populations, define therapeutic windows, monitor target engagement, and support dose adjustment or treatment discontinuation.

Future research should prioritize multicenter randomized trials with prespecified core efficacy and safety outcomes; standardized formulations and exposure-effect analyses; integrated preclinical toxicology and real-world pharmacovigilance; and internationally aligned manufacturing and regulatory standards. These elements should be embedded in stage- and biomarker-enriched designs to reduce biological heterogeneity and define benefit-risk boundaries. Although current evidence suggests possible myocardial protection through immune-inflammatory modulation, reduction of oxidative and mitochondrial injury, regulation of autophagy and cell death, and limitation of fibrosis, substantially more rigorous evidence is required before a clinical role can be established.

Conclusions

Viral myocarditis is driven by interacting viral injury, dysregulated immune-inflammatory responses, cardiomyocyte stress and death, and subsequent fibrotic remodeling. Natural products and herbal medicines may modulate several of these processes, but the available evidence is predominantly preclinical and human studies are limited by small samples, heterogeneous formulations, surrogate outcomes, and insufficient long-term safety assessment. These interventions should therefore be regarded as promising adjunctive therapeutic candidates rather than established treatments. Routine clinical implementation will require standardized products, validated biomarker-based patient stratification, and rigorous multicenter randomized controlled trials with clinically meaningful efficacy and safety outcomes.

Funding Statement

This project was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2024ZD0522000, 2024ZD0522001), Henan Province Key Research and Development Project (Grant No. 231111310200), and the National Natural Science Foundation of China (Grant No. 82505477).

Abbreviations

A20, tumor necrosis factor alpha-induced protein 3; AMPK, AMP-activated protein kinase; Akt, protein kinase B; ATP, adenosine triphosphate; AOPP, advanced oxidation protein products; APS, Astragalus polysaccharides; Arg1, arginase-1; AS-IV, Astragaloside IV; AST, aspartate aminotransferase; ATF4, activating transcription factor 4; ATG5, autophagy-related 5; ATG16L1, autophagy-related 16-like 1; B10/Breg, regulatory B cells; Bax, Bcl-2-associated X protein; BBR, berberine; Bcl-2, B-cell lymphoma-2; CAP, cholinergic anti-inflammatory pathway; CARD8, caspase recruitment domain-containing protein 8; CAT, catalase; CCL2, C–C motif chemokine ligand 2; CCL7, C–C motif chemokine ligand 7; CCR2, C–C chemokine receptor 2; CD3, cluster of differentiation 3; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CFs, cardiac fibroblasts; CHOP, C/EBP homologous protein; CK, creatine kinase; CK-MB, creatine kinase-MB; CO, cardiac output; CRP, C-reactive protein; CVB3, Coxsackievirus B3; CVF, collagen volume fraction; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CXCL10, C–X–C motif chemokine ligand 10; CXCR2, C–X–C chemokine receptor 2; CMR, cardiac magnetic resonance; DAMPs, damage-associated molecular patterns; DCM, dilated cardiomyopathy; DGBXD, Danggui Buxue Decoction; DJ-1, protein deglycase DJ-1; DL, dihydrolycorine; Dusp1, dual specificity phosphatase 1; E/A, early-to-late diastolic transmitral flow velocity ratio; ECG, electrocardiogram; ECM, extracellular matrix; EF, ejection fraction; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ERS, endoplasmic reticulum stress; ETC, electron transport chain; Fas/FasL, Fas/Fas ligand; FFA, free fatty acid; FOXO3, forkhead box O3; FS, fractional shortening; GABARAP, GABA type A receptor-associated protein; GPx, glutathione peroxidase; GRP78, glucose-regulated protein 78; GRP94, glucose-regulated protein 94; GSH, glutathione; GSH-Px, glutathione peroxidase; GST, glutathione S-transferase; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HE, hematoxylin-eosin; H-FABP, heart-type fatty acid-binding protein; HDAC, histone deacetylase; HMGB1, high mobility group box 1; HQG, Huangqi Granule; HW/BW, heart weight-to-body weight ratio; hs-CRP, high-sensitivity C-reactive protein; ICA, icariin; ICAM, intercellular adhesion molecule; IFN-γ, interferon-γ; IgA, immunoglobulin A; IgG, immunoglobulin G; IL, interleukin; IL-21R, interleukin-21 receptor; iNOS, inducible nitric oxide synthase; IRAK1, interleukin-1 receptor-associated kinase 1; IRF7, interferon regulatory factor 7; IVIG, intravenous immunoglobulin; JAK/STAT, Janus kinase/signal transducer and activator of transcription; JNK, c-Jun N-terminal kinase; LC3, microtubule-associated protein 1 light chain 3; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume; LVFS, left ventricular fractional shortening; LVPWd, left ventricular posterior wall thickness at end-diastole; MAC, membrane attack complex; MAPK, mitogen-activated protein kinase; Mb, myoglobin; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MHC-II, major histocompatibility complex class II; MIF, macrophage migration inhibitory factor; MMP-9, matrix metalloproteinase-9; MPO, myeloperoxidase; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; mTOR, mechanistic target of rapamycin; NBR1, NBR1 autophagy cargo receptor; NDP52, nuclear dot protein 52 kDa; NE, neutrophil elastase; NETs, neutrophil extracellular traps; NF-κB, nuclear factor kappa B; NK, natural killer; NLR, NOD-like receptor; NLRP3, NOD-like receptor family pyrin domain containing 3; NLRX1, NLR family member X1; NO, nitric oxide; NOX4, NADPH oxidase 4; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OMT, oxymatrine; OPN, osteopontin; PARP, poly(ADP-ribose) polymerase; PDCD4, programmed cell death 4; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PI3K, phosphoinositide 3-kinase; PI4P, phosphatidylinositol 4-phosphate; PINK1, PTEN-induced kinase 1; PLEKHM1, pleckstrin homology and RUN domain containing M1; PK, pharmacokinetics; PRRs, pattern-recognition receptors; Rap1, Ras-proximate-1; RLR, RIG-I-like receptor; RORγt, retinoic acid receptor-related orphan receptor-γt; ROS, reactive oxygen species; RCT, randomized controlled trial; S100A6, S100 calcium-binding protein A6; SOD, superoxide dismutase; SPP1, secreted phosphoprotein 1; STAT3, signal transducer and activator of transcription 3; STING, stimulator of interferon genes; STX17, syntaxin 17; SUMO, small ubiquitin-like modifier; SV, stroke volume; SNAP29, synaptosome-associated protein 29; TAXBP1, Tax1-binding protein 1; TBK1, TANK-binding kinase 1; TAS, total Astragalus saponins; TCM, traditional Chinese medicine; TFEB, transcription factor EB; TFRC, transferrin receptor; TGF-β, transforming growth factor-β; Th1, T helper 1; TIMP-1, tissue inhibitor of metalloproteinase-1; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; Treg, regulatory T cells; TRIM29, tripartite motif-containing 29; ULK, Unc-51-like autophagy activating kinase; UVRAG, UV radiation resistance-associated; VAMP8, vesicle-associated membrane protein 8; VCAM, vascular cell adhesion molecule; VEGF-C, vascular endothelial growth factor C; VEGFR3, vascular endothelial growth factor receptor 3; VMC, viral myocarditis; VP1, viral protein 1; WIPI2, WD repeat domain phosphoinositide-interacting protein 2; YQJDD, Yiqi Jiedu Decoction; ZGCD, Zhigancao Decoction; α7nAChR, alpha-7 nicotinic acetylcholine receptor.

Data Sharing Statement

All data supporting this review are contained within the article and Supplementary Material; no new primary dataset was generated.

Author Contributions

Wenjun Wu: Conceptualization; Methodology; Investigation; Data curation; Formal analysis; Visualization; Writing – original draft; Writing – review & editing.

Xue Li: Investigation; Data curation; Validation; Visualization; Writing – review & editing.

Rui Yu: Investigation; Data curation; Validation; Visualization; Writing – review & editing.

Bin Li: Methodology; Investigation; Data curation; Writing – review & editing.

Xinlu Wang: Methodology; Investigation; Validation; Visualization; Writing – review & editing.

Jingjing Wei: Conceptualization; Supervision; Project administration; Funding acquisition; Writing – review & editing.

Mingjun Zhu: Conceptualization; Supervision; Project administration; Funding acquisition; Writing – review & editing.

All authors gave final approval of the version to be published, agreed on the journal to which the article was submitted, and agreed to be accountable for all aspects of the work.

Disclosure

The authors of this study have no conflicts of interest.