Platycladus orientalis (L.) Franco leaves, first recorded in Shennong’s Classic of Materia Medica as a superior-grade herb, are the dried branch tips and leaves of the cypress family plant. According to traditional Chinese medicine theory, they are slightly cold in nature, bitter and astringent in taste, and act on the lung, liver, and spleen meridians. Their traditional uses include cooling blood to stop bleeding, resolving phlegm to relieve cough, and promoting hair growth. Clinically, they are used to treat hemoptysis, epistaxis, hematemesis, hematochezia, metrorrhagia, lung heat cough, and alopecia. Notably, P.orientalis leaves are not only a traditional Chinese medicinal material but also an approved health food ingredient by the National Medical Products Administration [1].

In recent years, the frequent emergence of viral infectious diseases has posed serious challenges to global public health. The outbreak of coronavirus disease 2019 (COVID-19) has highlighted the urgent need for antiviral drug development [2]. Traditional Chinese medicine has shown unique advantages in the prevention and treatment of viral diseases, and searching for highly effective, low-toxic antiviral active components from natural medicines has become an important research direction [3][4]. As an abundant traditional Chinese medicine resource, P.orientalis leaves have gradually attracted scholarly attention for their antiviral activities. Modern research has revealed that P.orientalis leaves contain various chemical components, including flavonoids, terpenoids, volatile oils, and polysaccharides, some of which exhibit promising antiviral activities [1][5].

This review comprehensively summarizes the research progress on the antiviral effects of P.orientalis leaves, analyzes their active components, mechanisms of action, quality control status, and discusses future research directions, aiming to provide a reference for further development and clinical application.

To ensure the quality control of P.orientalis leaf medicinal material, researchers have established HPLC fingerprint analysis methods. Wang et al. (2023) established HPLC fingerprints of P.orientalis leaves from different origins. A total of 13 common peaks were found in 24 batches of samples. Compared with the reference fingerprint, the similarity of 23 batches (except one batch of Juniperus chinensis leaves) was above 0.92. The study identified four common peaks: myricitrin, quercitrin, isoquercitrin, and amentoflavone. Chemical pattern recognition methods such as cluster analysis, principal component analysis, and partial least squares-discriminant analysis can be used for quality control and authentication of P.orientalis leaves [16]. Principal component analysis showed that six principal components had a cumulative variance contribution rate of 88.412%, which could reflect most of the information of the original chromatographic peaks [16]. Additional quality control studies for P.orientalis formulations have also been reported [17].

A critical question for antiviral development is whether these marker compounds are functionally linked to antiviral activity or serve merely as chemical markers. Table 2 addresses this question.

Table 2. Functional relevance of quality control marker compounds.

Taken together, none of the four marker compounds has been directly validated for antiviral activity specifically in P.orientalis. Quercitrin, the Pharmacopoeia indicator, was selected based on chemical abundance rather than functional relevance. Amentoflavone holds promise as a potential functional marker, but validation in P.orientalis is required.

These findings have important implications for future quality control. Ideally, quality specifications should prioritize compounds with demonstrated antiviral activity. The current reliance on non-activity-linked chemical markers is sufficient for authentication but inadequate for ensuring batch-to-batch consistency of antiviral efficacy. Future efforts should identify active compounds, validate them as functional markers, and incorporate them into updated quality standards.

These methods provide a scientific basis for improving the quality standards of P.orientalis leaf medicinal material. The establishment of comprehensive quality evaluation systems is essential for the development of P.orientalis leaves as a reliable source of antiviral agents. The application of chromatographic fingerprinting combined with chemometrics for quality control of traditional Chinese medicine has been well established [19].

In addition to the antiviral effects discussed above, P.orientalis leaves exhibit a range of other pharmacological activities that may complement their therapeutic potential. Anti-inflammatory effects of P.orientalis flavonoids have been reported, which could help mitigate virus-induced inflammatory responses [5]. The anti-inflammatory biomarkers of P.orientalis have been further characterized using UPLC/MS/MS and network pharmacology [18]. The antioxidant properties of P.orientalis components [1][15] may also contribute to tissue protection during viral infections. Furthermore, consistent with traditional use for hemostatic purposes, modern research has confirmed the ability of P.orientalis leaves to promote blood coagulation and shorten bleeding time [8]. These multifaceted activities suggest that P.orientalis leaves might serve as an adjunctive therapy for viral diseases complicated by inflammatory or hemorrhagic manifestations. The pharmacological effects of P.orientalis have been comprehensively reviewed [8]. For a broader context, research progress on antiviral mechanisms of traditional Chinese medicine in general has also been summarized [20], and the immunomodulatory effects of polysaccharides from traditional Chinese medicine have been reviewed [21].

Despite the promising anti-HBV activity observed in vitro, no systematic safety, toxicity, or pharmacokinetic (PK) studies have been reported for P.orientalis leaf extracts or their pure compounds, which represents a major barrier to clinical translation. Regarding toxicity, acute or subacute toxicity studies in animals are currently absent; traditional use suggests low toxicity, but this has not been quantified using modern toxicological standards. In terms of pharmacokinetics, based on studies of other plant sources, the key flavonoids found in P.orientalis (quercitrin, myricitrin, amentoflavone) are known to have very low oral bioavailability (typically <5%) due to poor absorption and rapid glucuronidation, and no PK studies have been conducted specifically on P.orientalis compounds. Furthermore, potential herb-drug interactions mediated by cytochrome P450 (CYP) enzymes (e.g., CYP3A4, CYP2D6, CYP1A2) have not been evaluated for P.orientalis extracts. Finally, no Phase I or Phase II clinical trials have been conducted to date. These limitations must be addressed before any clinical application can be seriously considered. This section is intended to provide a balanced perspective on the translational challenges facing the development of P.orientalis leaves as antiviral agents.

Although certain progress has been made in antiviral research on P.orientalis leaves, several challenges remain. Research on active components lacks sufficient depth; most work has focused on isolation and identification, while systematic antiviral activity screening and structure-activity relationship studies remain relatively underdeveloped. Although flavonoids and polysaccharides have demonstrated some anti-HBV activity, evaluations of individual monomeric compounds are still not systematic or comprehensive [5]. Mechanistic studies also require strengthening, as existing work is largely preliminary and lacks in-depth molecular target analysis. While immunomodulatory mechanisms have been explored using macrophage polarization models, the complexity of virus-host interactions demands investigation from multiple perspectives and levels. Furthermore, in vivo and clinical research are insufficient. Most current studies rely on in vitro experiments without systematic in vivo pharmacodynamic evaluation, leaving the clinical value of P.orientalis leaves’ antiviral effects to be further validated. The lack of standardized animal model studies limits the translation of in vitro findings to clinical applications. Quality control standards, though established, need further refinement to ensure batch-to-batch consistency for potential pharmaceutical development. As noted in Section 7, the complete absence of safety, toxicity, and pharmacokinetic data represents a critical barrier to clinical translation. Finally, in the context of the COVID-19 pandemic, the potential anti-coronavirus effects of P.orientalis leaves—a traditional Chinese medicine with recognized antiviral potential—have not been systematically studied, representing a significant research gap that warrants attention [2][3].

To advance the research on Platycladus orientalis leaves as an antiviral agent, several key directions should be pursued. First, activity-guided isolation and purification should be strengthened by establishing high-throughput antiviral activity screening models, which would enable the isolation and identification of antiviral active components based on activity guidance and help clarify the material basis of pharmacodynamic effects, with particular emphasis on in-depth investigation of the structure-activity relationships of flavonoids and polysaccharides. Second, the molecular mechanisms need to be elucidated using modern molecular biology techniques to clarify how active components exert antiviral effects at both the viral and host levels, including identification of their molecular targets. Immunological research methods, such as macrophage polarization models, can be employed to explore immunomodulatory mechanisms [5][11]. Omics approaches such as transcriptomics and proteomics could provide comprehensive insights into the mechanisms of action. Third, in vivo pharmacodynamic studies should be conducted by establishing viral infection animal models, such as HBV transgenic mouse models, to systematically evaluate the in vivo antiviral effects and safety of P.orientalis leaf extracts and their active components. Long-term toxicity studies are also needed to support potential clinical applications. Fourth, formulation development and clinical research should be promoted by developing new formulations based on the antiviral active components and conducting standardized clinical trials to provide a scientific basis for clinical use. The relevant patent for P.orientalis leaf polysaccharide has already laid a foundation for its industrial application [9]. The development of user-friendly formulations such as sprays [14] or oral preparations could facilitate clinical translation. Fifth, quality control standards must be improved by establishing a more scientific and comprehensive quality evaluation system based on HPLC fingerprinting and chemical pattern recognition methods, thereby ensuring stable and controllable quality of antiviral preparations [16][19]. Sixth, basic safety, toxicity, and pharmacokinetic studies are urgently needed before any preclinical or clinical development can proceed.

As a traditional Chinese medicine resource, P.orientalis leaves have shown preliminary confirmation of their antiviral activity, particularly against HBV. Flavonoids, terpenoids, and polysaccharides constitute the material basis for their antiviral effects, which may act through multiple pathways: direct inhibition of viral replication (demonstrated for HBV), modulation of immune responses (suggested by macrophage assays in the absence of viral infection), and antioxidant effects (not yet directly linked to antiviral activity). Among these, the anti-HBV activity of flavonoids and polysaccharides has been experimentally verified in HepG2.2.15 cells, and relevant patents have outlined their potential as adjuvant therapeutic agents for hepatitis B [5][9][11]. Regarding quality control, the establishment of HPLC fingerprinting combined with chemical pattern recognition methods provides a reliable means for quality evaluation [16][19]. However, current marker compounds have not yet been functionally linked to antiviral activity.

Key limitations that should be addressed in future research include: 1) the absence of in vivo animal studies; 2) the lack of safety and toxicity data; 3) the absence of pharmacokinetic studies; 4) the lack of direct evidence for antiviral activity against any virus other than HBV; and 5) the hypothetical nature of proposed mechanisms (immunomodulation, NK cell activation), which have not been validated in virus-infected models.

Although current research is still in the preliminary stage, the therapeutic potential of P.orientalis leaves in the antiviral field is beginning to emerge. With continued advances in modern analytical techniques and pharmacological research methods, research on the antiviral effects of P.orientalis leaves will deepen, potentially offering new options for the prevention and treatment of viral diseases. Future research should focus on systematic in vivo studies, mechanistic elucidation, safety, PK profiling, and clinical development to fully realize the therapeutic potential of this promising traditional Chinese medicine.

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