1 Introduction

Ganoderma lucidum (Lingzhi) has been at the heart of traditional Chinese medicine (TCM) for more than two thousand years, considered the "herb of immortality" due to its wide-ranging health benefits. It was conventionally prescribed to tonify qi, calm the spirit, and promote vitality. Modern pharmacological research has substantiated many of the traditional assertions, demonstrating that G. lucidum contains a rich array of bioactive constituents, including triterpenoids, polysaccharides, phenolic compounds, and sterols. These compounds contribute to its immunomodulatory, anti-inflammatory, antioxidant, anti-tumor, and hepatoprotective activities. The dual validation of Lingzhi by traditional practice and contemporary biomedicine testifies to its unique status as a nexus between ancient empirical knowledge and contemporary pharmacological science (Chiu et al., 2017).

A feature of TCM is multi-herb prescriptions, i.e., the use of botanicals in combination in the form of formulae according to synergy, balance, and mutual potentiating. The purpose of these herbal formulae is to maximize therapeutic effect with fewer side effects. Synergy between herbs can be due to a number of mechanisms, including additive or potentiated pharmacological effects, increased bioavailability, and modification of pharmacokinetic and pharmacodynamic processes (Ye et al., 2023). However, hostile or opposite interactions can also happen, and this explains the need for systematic research. As one of the most valued tonic herbs, G. lucidum is commonly combined in formula with other TCM herbs such as Astragalus, Ginseng, Lycium, and Salvia, where it is believed to enhance immune regulation, sustain cardiovascular function, protect neural function, and decelerate aging processes (Seweryn et al., 2021; Ding et al., 2024).

This study aims to analysis the synergistic activities of G. lucidum, when used in combination with other TCM drugs, particularly focusing on pharmacologic interactions. Specifically, it lays out the major bioactive constituents and pharmacological effects of G. lucidum, describes its synergism and antagonism with other traditional herbal medicines, and indicates the molecular mechanisms of such interactions. In addition, it discusses preclinical and clinical information, safety, and quality control matters. By incorporating evidence from both traditional practice and modern biomedical research, the review is expected to provide an overall picture of the pharmacological grounds of G. lucidum compounds, thereby offering theoretical instruction and practical reference for the creation of new herbal products and TCM modernization.

2 Major Bioactive Components and Pharmacological Effects of Ganoderma lucidum

2.1 Triterpenoids

Triterpenoids, especially ganoderic acids, are among the most abundant, and have relatively good pharmacological activity components in Ganoderma lucidum. More than 100 different triterpenoids have been identified so far, among which ganoderic acid A has been the most extensively studied. These compounds exhibit a variety of biological activities, including anti-cancer, anti-inflammatory, liver-protective, neuroprotective and antiviral effects.

In terms of mechanism of action, triterpenoids can induce apoptosis, block the cell cycle, inhibit topoisomerase activity, and regulate signaling pathways, such as mTOR and JAK-STAT3, thereby exerting their anti-tumor and cell-protective effects (Ahmad et al., 2022; Peng et al., 2023; Wang et al., 2024).

2.2 Polysaccharides

Polysaccharides, like β -glucan, are the main water-soluble active components in G. lucidum. Polysaccharides are renowned for their immunomodulatory effects, and can enhance innate and adaptive immune responses, by activating macrophages, dendritic cells and T lymphocytes. Polysaccharides also possess multiple activities, containing anti-tumor, anti-oxidation, anti-diabetes, liver protection and neuroprotection. Its mechanisms of action include regulating cytokine production, inducing apoptosis of cancer cells, and regulating oxidative stress and metabolic pathways (Zeng et al., 2018; Ahmad et al., 2021; Gao and Homayoonfal, 2023).

2.3 Phenolic compounds and sterols

G. lucidum contains a variety of phenolic compounds and sterols, such as ergosterol, which contribute to its antioxidant, anti-inflammatory and neuroprotective effects. Phenolic compounds, including quercetin and oleanolic acid, are associated with acetylcholinesterase inhibition and free radical scavenging, which contribute to neuroprotection, and reduce oxidative damage. Sterols can also regulate immune responses, and may play a role in the overall therapeutic effect of G. lucidum (Sheikha, 2022; Lian et al., 2024).

2.4 Pharmacological activities: immunomodulatory, anti-inflammatory, antioxidant, etc.

G. lucidum exhibits a wide range of pharmacological activities, mainly attributed to its rich content of polysaccharides, triterpenoids, phenolic compounds and sterols. Its immunomodulatory effect has been widely studied. β -glucan and other polysaccharides can enhance innate, and adaptive immunity by activating macrophages, dendritic cells and natural killer cells, as well as regulating cytokine production and lymphocyte activity (Peng et al., 2023).

The anti-inflammatory effect of G. lucidum, is mainly achieved by inhibiting key inflammatory mediators, such as TNF-α, IL-6 and COX-2, as well as suppressing the NF-κB and MAPK signaling pathways. Both triterpenoids and sterols are involved in this process. Studies have shown that, they can reduce the expression of pro-inflammatory cytokines and enzymes in various cell and animal models (Zeng et al., 2018; Ahmad, 2020; Chen et al., 2024; Lian et al., 2024; Liu et al., 2024).

Antioxidant activity is another important characteristic of G. lucidum. Its active ingredients can effectively eliminate free radicals, reduce lipid peroxidation, and enhance the activities of endogenous antioxidant enzymes, like superoxide dismutase and glutathione peroxidase, thereby protecting cells from oxidative stress and related damage (Ding et al., 2024). These pharmacological effects support the application of G. lucidum in the prevention and management of chronic diseases related to immune dysfunction, inflammation and oxidative stress, and provide a mechanism basis for its traditional health care, and disease prevention and treatment uses (Sanodiya et al., 2009; Cadar et al., 2023; Ahmad et al., 2024) (Figure 1).

Figure 1 Various pharmacological effects of Ganoderma lucidum as a health promoter (Adopted from Ahmad et al., 2024)

3 Types of Synergistic Interactions between G. lucidum and Other Chinese Medicinal Herbs

3.1 Synergistic enhancement

The synergistic enhancement effect refers to the situation, where the total therapeutic effect produced when G. lucidum is used in combination with other traditional Chinese medicines exceeds the sum of the individual effects of each component or shows a multiplier effect. For instance, the combination of G. lucidum and Panax notoginseng has been proven to have a synergistic effect in lowering blood lipids. The mechanism includes the coordinated action through targets, such as PepT1 and PPARα, to enhance drug absorption and lipid regulatory activity (Qiao et al., 2017; Dong, 2024).

In co-culture studies, G. lucidum co-cultured with ginseng demonstrated superior mycelial growth and more effective degradation of plant cell wall components, suggesting that certain combinations of medicinal materials, can improve the bioavailability and utilization efficiency of active components. These research results support the rationality of multi-drug combinations in traditional Chinese medicine, that is, the therapeutic effect can be amplified through drug combinations.

3.2 Antagonistic effects and potential risks

Not all combinations are beneficial. In some cases, antagonistic effects may occur, that is, certain medicinal materials inhibit the growth or activity of G. lucidum, or reduce the combined therapeutic effect. For example, when co-cultured with kirilow rhodiola root, the mycelial growth of G. lucidum was weaker than when co-cultured with ginseng or reed root, suggesting that some combinations may inhibit the development or function of G. lucidum, thereby potentially reducing the therapeutic effect (Peng et al., 2023; Lian et al., 2024). These antagonistic effects emphasize the importance of selecting medicinal materials, and evaluating their compatibility in the design of traditional Chinese medicine compound prescriptions, to avoid reduced efficacy or unexpected adverse reactions.

3.3 Pharmacokinetic and pharmacodynamic interactions

Pharmacokinetic interactions, refer to the changes in the absorption, distribution, metabolism or excretion of active ingredients, when G. lucidum is used in combination with other medicinal materials. For example, the synergistic mechanism of G. lucidum and Panax notoginseng, partly attributed to enhanced absorption through PepT1, and increased lipid-lowering activity through PPARα activation, shows how targeted interactions can improve pharmacokinetic properties (Qiao et al., 2017; Zhang, 2024).

Pharmacodynamic interactions, refer to the synergistic effects, produced by the combination on biological targets or signaling pathways, including enhancing immunomodulatory, anti-inflammatory or antioxidant activities, etc. This is reflected in many traditional Chinese medicine compound prescriptions, but the specific results depend on the compatibility of the medicinal materials and the mechanism of action (Ahmad et al., 2024).

4 Studies on Synergistic Effects of G. lucidum with Common Chinese Medicinal Herbs

4.1 G. lucidum with astragalus membranaceus: immunomodulation and antitumor effects

Evidence is appearing that G. lucidum polysaccharides and Astragalus membranaceus astragalosides both have the capacity to enhance immune responses and induce proliferation and differentiation of neural stem cells. This has been reported to lay the foundation for synergistic immunomodulatory and neuroprotective effects when used in combination but most of this evidence is on the basis of preclinical trials and conclusive clinical evidence of their combined antitumor or immunomodulatory activity is limited (Chen et al., 2024).

4.2 G. lucidum with panax ginseng: antifatigue and neuroprotective effects

Co-cultivation experiments prove that G. lucidum and Panax ginseng used in combination promote mycelial growth and plant cell wall component degradation, which can further promote the bioavailability of active components. The ginsenosides and G. lucidum polysaccharides have been proven to upregulate the neurotrophic factors, relieve oxidative stress, and promote neural regeneration, allowing them to be applied in combination for antifatigue and neuroprotection effects (Chen et al., 2025).

4.3 G. lucidum with lycium barbarum: antioxidant and anti-aging effects

Though there are no explicit studies on Ganoderma lucidum and Lycium barbarum in combination in recent literature, both are extremely antioxidant-dense herbs. Their polysaccharides are said to reduce oxidative stress, and it is possible that their combined use has a synergistic effect in promoting antioxidant and anti-aging effects, but more specific studies are needed to confirm such interactions (Chen et al., 2025).

4.4 G. lucidum with salvia miltiorrhiza/angelica sinensis: cardiovascular and circulatory improvement

Synergic effects on lipid metabolism and cardiovascular disease have been observed in combined therapy, mediated by target interaction with PepT1 and PPARα. G. lucidum and Salvia officinalis, which are closely related plants, also exhibit strong synergism in antioxidant and antineurodegeneration, suggesting circulatory and neuroprotective benefit (Qiao et al., 2017; Ćilerdžić et al., 2019).

5 Molecular Mechanisms of Synergistic Actions

5.1 Regulation of signaling pathways

Synergistic interactions of Ganoderma lucidum with other herbs of TCM can modulate significant cellular cascades of signaling. Ganoderma lucidum polysaccharides (GLPs) have been shown to regulate the NF-κB pathway, central to inflammation and immunity, and the MAPK and PI3K-Akt pathways, critical in cell survival, growth, and death. These regulatory effects contribute to enhanced anti-inflammatory, antitumor, and neuroprotective properties when Ganoderma lucidum is used in conjunction with other herbs (Lu et al., 2020; Jiang et al., 2024).

5.2 Modulation of immune cell functions

GLPs alone and in synergy with other TCM herbs can regulate the activity of various immune cells, including T lymphocytes, natural killer (NK) cells, and macrophages. These extend from cytokine production induction to phagocytic function and cytotoxicity against cancer cells. Such immune cell function regulations are the cornerstone of immunoregulatory and antitumor benefits in multi-herb formulations (Lu et al., 2020; Luo et al., 2021).

5.3 Regulation of oxidative stress and inflammatory responses

Ganoderma lucidum and their formulational blends with other herbs exert strong antioxidant actions by scavenging free radicals and stimulating endogenous antioxidant enzymes. They also suppress inflammatory responses through inflammasome blockage and downregulating pro-inflammatory cytokine transcription, normally through the NF-κB and NLRP3 pathways. These mechanisms also provide protective functions against oxidative insult and chronic inflammation (Lu et al., 2020; Ding et al., 2024).

5.4 Roles of metabolomics and gut microbiota

Current evidence highlights the involvement of metabolomics and gut microbiota in mediating synergistic action of Ganoderma lucidum with other TCM herbs. GLPs can regulate the composition of gut microbiota, which has a ripple effect on immune and metabolic pathways. Metabolomic profiling shows that such combinations can influence the levels of key metabolites, resulting in their therapeutic effects, such as neuroprotection and metabolic regulation (Jiang et al., 2024).

6 Advances in Clinical and Experimental Studies of Ganoderma lucidum with TCM Herbs

6.1 Findings from in vitro and animal studies

A large number of in vitro and animal experiments have shown that G. lucidum, especially its polysaccharides and triterpenoids, have obvious antioxidant, anti-inflammatory, immunomodulatory and anti-tumor effects. For instance, G. lucidum polysaccharides alleviate cognitive dysfunction in animal models, by inhibiting neuroinflammation mediated by the NLRP3/NF-κB signaling pathway, and regulating the composition of the gut microbiota (Cadar et al., 2023; Jiang et al., 2024).

In cardiovascular research, G. lucidum polysaccharides can regulate lipid metabolism, reduce oxidative stress, and improve endothelial function in animal models of atherosclerosis. Co-culture studies with traditional Chinese medicines, like ginseng, have shown that the combination of G. lucidum with other medicinal materials, can promote the degradation of plant cell wall components, and enhance the bioavailability of active ingredients (Figure 2).

Figure 2 Bioactive compounds in lentinan and their biological effects related to antitumor activity (Adopted from Cadar et al., 2023)

6.2 Clinical applications and examples of herbal formulae

Although the number of clinical studies is relatively small, there is already evidence that G. lucidum supplements can enhance the body's antioxidant capacity, reduce oxidative stress and support liver health. A randomized, double-blind, placebo-controlled trial found that G. lucidum, is rich in triterpenoids and polysaccharides could improve plasma antioxidant indicators, and reverse mild fatty liver status in healthy volunteers (Chiu et al., 2017).

In addition, supplementation of G. lucidum dry extract can regulate T lymphocyte function, and promote anti-inflammatory immune response in elderly women (Iser-Bem et al., 2024). Though G. lucidum is often included in traditional Chinese medicine prescriptions for metabolic, liver and immune-related diseases, standardized clinical evidence for specific combinations remains limited.

6.3 Evidence and limitations from evidence-based medicine

In vitro and some clinical studies support the therapeutic potential of G. lucidum and its combination with traditional Chinese medicine, but there is still a lack of large-scale and high-quality clinical trial evidence. Studies have pointed out that, the health benefits observed in animal and in vitro experiments, are not always consistently replicated in human trials, which may be related to differences in formulations, dosages and study populations (Chan et al., 2021; Swallah et al., 2023).

Besides, methodological limitations, small sample sizes, and the lack of standardization in TCM preparations are common problems. More rigorously designed and well-sample clinical studies, are needed in the future to confirm the efficacy, and safety of G. lucidum compound in different patient populations (Wu et al., 2023).

7 Safety and Quality Control

7.1 Safety assessment of combined use of Ganoderma lucidum with other herbs

Recent studies have shown that Ganoderma lucidum, whether used alone or in combination with other traditional Chinese medicines, usually has good safety. In long-term toxicity experiments on animals, no significant systemic toxicity was observed even when high-dose despore layer Ganoderma lucidum spores were used, and the no-observed-adverse-effect level (NOAEL) was much higher than the conventional human dose (Xia et al., 2023). The comprehensive review, also pointed out that the products based on Ganoderma lucidum had good tolerance, and there were few reports of serious adverse reactions in vitro, animal experiments and clinical studies (Swallah et al., 2023).

7.2 Potential herb-drug interactions and adverse effects

Ganoderma lucidum is considered safe, but potential drug-herbal interactions and mild adverse reactions still need attention, especially when used in combination with other herbs or drugs. It has been reported that, adverse events such as mild gastrointestinal discomfort may occur, but severe toxicity is rare (Swallah et al., 2023; Wu et al., 2023). The complexity of multiple herbal compound prescriptions increases the risk of unpredictable interactions. When Ganoderma lucidum is used in combination with other traditional Chinese medicines, the pharmacokinetics of the active ingredients may change. So, especially for patients who are taking other medications, careful monitoring should be conducted and professional medical personnel should be consulted.

7.3 Quality control and standardization challenges of herbal formulae

The quality control and standardization of Ganoderma lucidum and its compound preparations remain major challenges. The efficacy and safety depend on the consistency of the active ingredients. But, due to species differences, cultivation conditions, extraction methods and processing techniques, there may be fluctuations in the active ingredients (Plosca et al., 2025).

The application of advanced technologies such as ultrasonic and microwave-assisted extraction, has increased the yield and bioavailability of active ingredients, but the standardized operation procedures are still not perfect. To ensure the safety, efficacy and reproducibility of G. lucidum and its compound products, it is crucial to establish a sound regulatory framework, and adopt drug-grade quality assurance methods (Swallah et al., 2023).

8 Concluding Remarks

Over the past decades, more and more evidence has indicated that Ganoderma lucidum (Lingzhi) produces impressive pharmacological activities when it is used with other traditional Chinese medicinal (TCM) herbs. Data highlight its capacity to synergize with herbs such as Astragalus, Ginseng, Lycium, and Salvia, triggering enhanced immune modulation, anti-tumor activity, neuroprotection, cardiovascular protection, and anti-aging activity. Mechanistic research shows that these synergistic phenomena are mediated through the modulation of multiple signaling pathways (e.g., NF-κB, MAPK, PI3K-Akt), immune cell functions, reduction of oxidative stress, and interaction with metabolic as well as gut microbiota networks. Collectively, these findings validate the ancient TCM practice of coprescribing Lingzhi with other herbs to maximize therapeutic efficacy.

Studies on G. lucidum in polyherbal prescriptions emphasize the supreme significance of synergistic principles in TCM. Its diverse bioactive compounds not only provide direct pharmacological activities but also function as modulators that enhance the bioavailability and functional activities of concurrently ingested herbs. From a modern pharmacological perspective, such synergy provides a rationale for rational herbal formula design and drug discovery. Integration of traditional empirical wisdom with scientific validation improves the implementation of standardized compound formulas, boosts quality control, and provides an evidence base for clinical application. G. lucidum is therefore both a cornerstone of TCM heritage and a viable candidate for modern integrative medicine.

Future research must use cutting-edge methods to further elucidate synergistic mechanisms of G. lucidum together with other herbs. Multi-omics techniques-genomics, transcriptomics, proteomics, metabolomics, and microbiome analysis-will be essential for uncovering molecular networks underlying pharmacological interactions. In the meantime, integration of clinical big data and real-world evidence can provide robust evidence on safety, efficacy, and patient-specific outcomes. Tailor-made treatment, according to biomarkers and constitutional types, can potentially customize herbal combinations for optimal therapeutic outcomes. Lastly, the establishment of synergy studies on G. lucidum will not only promote TCM modernization but also the global development of evidence-based herbal medicine.

Acknowledgments

The authors extend heartfelt gratitude to the research team for their invaluable support in data collection and documentation, whose contributions ensured the successful completion of this study. Special appreciation is due to the two anonymous peer reviewers whose insightful comments and expert advice played a pivotal role in refining this research.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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