Abstract
Traditional Chinese medicine (TCM) has a long history of treating viral diseases through holistic approaches and multi-component formulations. In response to emerging global viral threats like coronavirus disease-2019 (COVID-19), TCM has demonstrated significant potential in both antiviral and immune-modulatory roles. This review summarizes the current state of TCM antiviral research, highlighting advances in identifying active components and elucidating their mechanisms, which include direct viral inhibition and immune regulation. Technological innovations, including artificial intelligence (AI)-driven drug discovery and advanced extraction methods, are accelerating the development of TCM antiviral products. However, challenges remain in standardization, mechanistic validation, and international regulatory acceptance. Looking ahead, research should prioritize systems pharmacology, the development of multi-dimensional evaluation models, standardized clinical trials, and global health integration. By addressing these challenges, TCM can play a vital role in worldwide antiviral strategies and public health.
Keywords: active components, antiviral research, internationalization, multi-dimensional models, systems pharmacology, traditional Chinese medicine, technological innovation
1. Introduction
Viral diseases such as coronavirus disease-2019 (COVID-19), influenza, and dengue continue to threaten global public health (Le Sage et al., 2023, Nakamura et al., 2022, Nazareth et al., 2023, Safiabadi Tali et al., 2021). The World Health Organization (WHO) has emphasized the need for diversified antiviral strategies, including traditional medicine systems like traditional Chinese medicine (TCM) (World Health Organization, 2013, World Health Organization., 2022). Rooted in ancient texts such as the Huangdi’s Internal Classic, TCM emphasizes balancing the body’s resistance (healthy qi) and external pathogens (pathogenic qi) (Curran, 2008). This approach aligns with modern immunology and has been applied in outbreaks from severe acute respiratory syndrome (SARS) to COVID-19 (Liu, 2020, Su et al., 2022).
The theoretical basis of TCM for the management of infectious diseases is firmly grounded in the warm diseases theory. This theory provides frameworks like defense-qi-nutrient-blood syndrome differentiation and triple-energizer syndrome differentiation, which guide the diagnosis and treatment of epidemic diseases, including viral respiratory infections (Li, Li, Liu, Tian, & Cui, 2021). The holistic paradigm of TCM aims not only to clear pathogens but also to regulate the body’s internal balance and enhancing immune function, which is particularly relevant in managing complex viral infections.
TCM formulations such as Lianhua Qingwen Capsules have shown efficacy in reducing symptom duration and severity (Hu et al., 2021, Xu et al., 2023, Zheng et al., 2023, Zhuang et al., 2021). The multi-component, multi-target nature of TCM offers advantages over single-target antivirals, potentially reducing drug resistance (Gan et al., 2023, Yang et al., 2025). Despite progress, issues like standardization and international regulatory barriers must be addressed to integrate TCM into global health frameworks (Fig. 1).
Fig. 1.
Overview of antiviral research in TCM: A pathway from tradition to modernization.
2. Current status of TCM antiviral research
2.1. Active components and mechanisms
TCM herbs contain bioactive compounds—flavonoids, alkaloids, terpenoids, polysaccharides—with demonstrated antiviral effects (Devi & Sarala, 2021). For example, chlorogenic acid from Lonicera japonica Thunb. inhibits influenza virus adsorption and suppresses viral protein expression (Ding, Cao, Cao, Ding, Wang, & Xiao, 2017). Berberine from Coptis chinensis Franch. suppresses hepatitis B virus (HBV) replication by inhibiting viral DNA polymerase and reduces hepatitis C virus (HCV) replication by targeting non-structural protein 5B (NS5B) polymerase (Hung et al., 2019, Yamashita et al., 2024). Quercetin regulates macrophage polarization through the succinate dehydrogenase (SDH)/hypoxia-inducible factor-1α (HIF-1α)/NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway, exerting both antiviral and anti-inflammatory effects (An et al., 2024, Kandeil et al., 2021, Wu et al., 2024). Representative antiviral constituents derived from TCM are summarized in Table 1.
Table 1.
Representative antiviral compounds derived from TCM.
| Compound class | Active ingredients | TCM source | Virus | Targets pathways | References |
|---|---|---|---|---|---|
| Flavonoids | Baicalin | Scutellaria baicalensis Georgi | Influenza A virus subtype H9N2 | Myxovirus resistance protein 1; Protein kinase R | Liu, Guo, Zhi, Jiang, & Zhang, 2025 |
| Hyperin; Quercitrin | Houttuynia cordata Thunb. | Influenza A virus subtype H1N1 | Neuraminidase; Toll-like receptor | Ling et al., 2020 | |
| Ginkgolide | Ginkgo biloba L. | SARS-CoV-2 | 3C-like protease (3CLpro) | Xiong et al., 2021 | |
| Scutellaria barbata D. Don extracts | Scutellaria barbata D. Don | SARS-CoV-2 | 3CLpro; Papain-like protease | Ran et al., 2025 | |
| Alkaloids | Ephedra alkaloids | Ephedra sinica Stapf | H1N1 | Toll-like receptor | Wei et al., 2019 |
| Epigoitrin | Isatis indigotica Fortune | H1N1 | Interferon-β; Interferon-induced transmembrane protein 3 | Luo et al., 2019 | |
| Eugenol | Syzygium aromaticum (L.) Merr. & L.M.Perry | Influenza A virus (IAV) | Beclin1-B-cell lymphoma 2 complex | Dai et al., 2013 | |
| Terpenoids | Saikosaponin C | Bupleurum chinense DC. | HBV | Hepatocyte nuclear factor 1α (HNF1α); HNF4α | Pan et al., 2019 |
| Andrographolide | Andrographis paniculata (Burm.f.) Nees | SARS-CoV-2 | Angiotensin-converting enzyme 2 | Sa-Ngiamsuntorn et al., 2021 | |
| Polysaccharides | Lysimachia christinae polysaccharides | Lysimachia christinae Hance | Pseudorabies virus (PRV) | Reactive oxygen species; Malondialdehyde |
Wang et al., 2025 |
| Astragalus polysaccharides | Astragalus membranaceus (Fisch.) Bunge | Coxsackievirus B3 (CVB3) | Toll-like receptor 4; Nuclear factor-κB subunit p65 | Liu et al., 2019 |
2.2. Immunomodulatory and host-directed mechanisms
TCM exerts antiviral effects not only through direct viral inhibition but also by comprehensively modulating host immune responses and repairing virus-induced tissue damage, which is central to its holistic advantage. It regulates cellular, humoral, and innate immunity (e.g., modulating T-cell subsets and macrophage function), modulates gut microbiota via the gut-lung axis to reduce lung inflammation and viral load, and alleviates tissue damage through anti-inflammatory actions (e.g., mitigating pulmonary fibrosis and myocardial injury), demonstrating its multi-target and holistic regulatory therapeutic advantages.
2.3. Clinical applications and efficacy
TCM has demonstrated significant clinical value, particularly during the COVID-19 pandemic. The National Health Commission of China recommended several TCM formulations, including Lianhua Qingwen Capsules, Jinhua Qinggan Granules, Xuebijing Injection, Qingfei Paidu Decoction, Huashi Baidu Formula, and Xuanfei Baidu Formula (collectively known as Three Medicines and Three Formulae) (Gao, Xiao, Fan, Zhang, Zhu, & Lv, 2022).
During the COVID-19 pandemic, a multicenter clinical trial showed that Lianhua Qingwen significantly reduced the time to symptom resolution (4.0 d vs 6.7 d in controls) and improved computed tomography (CT) findings (Zheng et al., 2023). Another study of severe COVID-19 patients found that integrated TCM-Western medicine treatment reduced mortality and improved lung function (Chen et al., 2020). For influenza, a meta-analysis of randomized controlled trials (RCTs) demonstrated that TCM monotherapy or combined with oseltamivir reduced fever duration, cough duration, and sore throat duration compared to oseltamivir alone (Chen et al., 2011, Li et al., 2016). In chronic HBV treatment, meta-analysis of RCTs showed TCM combined with conventional therapy significantly increased hepatitis B e antigen (HBeAg) seroconversion rates and normalized alanine aminotransferase (ALT) levels (Ge et al., 2023, Li et al., 2020, Yeo et al., 2019).
3. Technological innovations
3.1. Advanced extraction and biotechnology
Modern extraction technologies have significantly improved efficiency. Supercritical fluid extraction (SFE) of chlorogenic acid from L. japonica under optimized conditions increased extraction yield by 20%–40% compared to traditional ethanol reflux methods (Wu et al., 2013). Microwave-assisted extraction (MAE) of berberine from C. chinensis reduced extraction time from 2 h to 2 min (Belwal et al., 2020). Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing has been used to knockout genes involved in catabolism of active components. A study developed a tRNA-gRNA multiplex CRISPR/Cas9 system driven by the endogenous Solanum melongena ribosomal protein S5A (SmRPS5A) promoter, which significantly enhanced genome editing efficiency in Salvia miltiorrhiza Bge. (Danshen in Chinese, with an average of > 90% for single target, > 70% for double targets, and > 60% for triple targets) and homozygous mutation rates (> 20%) (Zheng et al., 2025). Similarly, similar techniques can significantly increase the active components in Macleaya cordata (Willd.) R. Br. (Sun et al., 2024).
3.2. Developing multi-dimensional evaluation models
A key research strategy is establishing models that accurately reflect the complexity of viral infection and TCM’s holistic effects. Moving beyond traditional 2D cell cultures, human respiratory organoids (e.g., lung, airway, nasal organoids) and air–liquid interface (ALI) cultures better mimic the structure and function of the respiratory epithelium, providing more physiologically relevant systems for studying virus-host interactions and drug screening (Wang et al., 2025). These models integrate specific TCM syndrome patterns with modern pathological features of a disease. They are crucial for evaluating TCM efficacy in a context that reflects its diagnostic theory, helping to bridge the gap between traditional concepts and modern biomedical research.
3.3. Systems pharmacology and multi-omics integration
To decipher the multi-component, multi-target, multi-pathway nature of TCM formulas, systems approaches are essential. Integrating transcriptomics, proteomics, metabolomics, and spatial metabolomic imaging allows for a comprehensive analysis of how TCM formulations affect gene expression, protein function, and metabolic networks during viral infection. This helps map the distribution and metabolic fate of active components within the body. Artificial intelligence (AI)-driven platforms have screened libraries of many TCM-derived compounds, identifying candidates with IC50 values in the nanomolar range against influenza virus (Cao et al., 2024, Yang et al., 2025). Network pharmacology analysis of Yin Qiao San identified active components and potential targets involved in antiviral, anti-inflammatory, and immune-regulatory pathways (Cao et al., 2022).
4. Internationalization prospects and challenges
Research is increasingly demonstrating the scientific basis of TCM antivirals. AI-driven screenings and network pharmacology analyses consistently identify numerous active ingredients and potential targets involved in antiviral and immunomodulatory pathways (Kang et al., 2020, Lai et al., 2020, Yang et al., 2025). Successful international multicenter clinical trials, such as those for Lianhua Qingwen Capsules, mark positive steps toward global recognition.
However, significant challenges persist for international integration. These include the standardization of complex multi-herb formulations, the need for rigorous and transparent clinical trials that meet international standards to validate efficacy and safety, and navigating diverse international regulatory frameworks that may not be designed for polypharmaceutical agents. The inherent complexity of elucidating and communicating the synergistic mechanisms of multi-component formulas remains a major hurdle for widespread scientific acceptance.
5. Future research directions
Priority areas include AI-driven drug discovery, systems pharmacology for formula mechanism elucidation, and development of broad-spectrum antiviral TCM formulations (Zheng et al., 2022, Zhou et al., 2024). Clinical translation should emphasize adaptive trial designs, syndrome-based stratification, and international multicenter trials (Wu, Wang, Bai, Chen, Hu, & Zhang, 2023).
To advance the internationalization of multi-herb products, future research should establish stepwise frameworks for collaboration with regulatory authorities, such as the WHO, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Key components may include internationally accepted quality and standardization criteria, harmonized preclinical and clinical evaluation strategies that address the multi-component nature of polyherbal formulations, early regulatory scientific advice to clarify evidentiary requirements, and tailored guidance for benefit risk assessment and post-marketing surveillance. Collectively, these efforts could facilitate the global development of TCM products while ensuring safety, efficacy, and regulatory transparency.
6. Conclusion
TCM offers a valuable, holistic approach to antiviral therapy supported by both historical practice and modern scientific validation. Its strengths lie in multi-target intervention, immune modulation, and systemic recovery, as evidenced in the management of respiratory viral infections including COVID-19. With ongoing technological innovation—such as AI, multi-omics, and advanced modeling—and enhanced international cooperation, TCM has the potential to contribute significantly to global antiviral efforts and public health. By addressing existing challenges in standardization, mechanistic clarity, and regulatory harmonization, TCM can be further integrated into worldwide strategies for pandemic preparedness and treatment, ultimately embodying a synergy of traditional wisdom and contemporary science.
CRediT authorship contribution statement
Kexin Wang: Writing – original draft - review & editing, Data curation, Methodology, Formal Analysis Validation. Zifeng Yang: Conceptualization, Supervision, Project administration, Founding acquisition.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine (No. ZYYCXTD-D-202406); National Natural Science Foundation of China (No. 82404916, 82341099); Science and Technology Development Program of Guangdong Province (No. 2025B1212030002); Guangdong Engineering Technology Research Center (No. 2024A137); Engineering Technology Research (Development) Center of Ordinary Colleges and Universities in Guangdong Province (No. 2024GCZX010).
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