Study on the Mechanism of Mahuang Xixin Fuzi Decoction in Treating AR and Prediction of Its Q-Markers Based on Network Pharmacology and Molecular Docking

• Abstract
• Introduction
• Methods
• Screening of Chemical Components in Mahuang Xixin Fuzi Decoction
• Target Gene Screening
• Construction of Protein–Protein Interaction Network
• Enrichment Analysis
• Molecular Docking Validation
• Results
• Main Components and Targets of Mahuang Xixin Fuzi Decoction
• Screening of Allergic Rhinitis Targets and Identification of Intersection Targets
• Protein–Protein Interaction Network Analysis
• Enrichment Analysis Results
• Molecular Docking Validation
• Discussion
• Conclusions
• References

Abstract

Objective

This study aimed to investigate the potential mechanism of Mahuang Xixin Fuzi Decoction in treating allergic rhinitis (AR) and predict its quality markers (Q-markers) using network pharmacology and molecular docking techniques.

Methods

The chemical components of the herbal constituents in Mahuang Xixin Fuzi Decoction were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Active component-related targets were screened using the SwissTargetPrediction database, while AR-related targets were obtained from the GeneCards database. The intersection targets (potential therapeutic targets of the Mahuang Xixin Fuzi Decoction for AR) were identified via the Venn 2.1.0 platform, and a Venn diagram was constructed. A “herb–active component–potential target” network was established using Cytoscape 3.10.0, and core components were screened via topological analysis. Protein–protein interaction (PPI) network of the intersection targets was built using the String database, followed by topological analysis to identify core targets. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the core targets using the DAVID database. Molecular docking of core components and targets was conducted using AutoDock Tools 1.5.7.

Results

Twenty-seven active components were identified from TCMSP, with 506 corresponding targets predicted by SwissTargetPrediction. A total of 2,447 AR-related targets were retrieved from GeneCards, yielding 165 intersection targets. Network analysis revealed naringenin, genkwanin, deoxyandrographolide, karakoline, and karanjin as core components. PPI network analysis identified 32 core targets. GO enrichment analysis screened 834 functional items, including 618 biological processes, 72 cellular components, and 144 molecular functions. KEGG analysis identified 165 signaling pathways. Molecular docking confirmed stable binding between core components and key targets.

Conclusion

Multiple chemical components in Mahuang Xixin Fuzi Decoction may ameliorate AR by regulating diverse targets and biological processes. Naringenin, genkwanin, and deoxyandrographolide are proposed as potential Q-markers for this decoction in AR treatment.

Introduction

Mahuang Xixin Fuzi Decoction is a classic prescription in traditional Chinese medicine (TCM) for treating the syndrome of concurrent Taiyang and Shaoyin diseases. It originates from Zhongjing Zhang's Treatise on Cold Damage (Shang Han Lun), which states: “For Shaoyin disease with initial onset, presenting with fever and sunken pulse, Mahuang Xixin Fuzi Decoction should be prescribed.” This decoction is primarily used to treat syndromes such as yang deficiency with cold congelation and cold transformation of Shaoyin. With the advancement of modern research, its clinical applications have expanded significantly. It is now widely used in respiratory diseases such as pneumonia,[1] asthma,[2] [3] and cardiovascular diseases.[4] [5] [6] [7] Studies have found that Mahuang Xixin Fuzi Decoction can also be applied to treat allergic rhinitis (AR) caused by deficiency-cold.[8] [9] [10] [11] [12] There is extensive literature on the mechanism of Mahuang Xixin Fuzi Decoction in treating AR. Based on this, this study aims to systematically analyze the potential therapeutic targets and related signaling pathways of Mahuang Xixin Fuzi Decoction in AR treatment using network pharmacology, with the goal of precisely elucidating its molecular mechanisms and predicting potential quality markers (Q-markers). Additionally, molecular docking will be employed to validate the binding affinity between key active components and core target proteins so as to provide a scientific basis for further research and clinical applications.

Methods

Screening of Chemical Components in Mahuang Xixin Fuzi Decoction

The chemical components of Mahuang (Ephedrae Herba), Fuzi (Aconm Lateralis Radix Praeparaia), and Xixin (Asari Radix et Rhizoma) were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP, https://old.tcmsp-e.com/tcmsp.php) using the respective herb names as keywords. Active components were screened based on the following criteria: molecular weight ≤500, lipid–water partition coefficient (AlogP) ≤5, number of hydrogen bond donors (Hdon) ≤5, number of hydrogen bond acceptors (Hacc) ≤10, oral bioavailability (OB) ≥30%, and drug-likeness (DL) ≥0.18. Targets of the active components were predicted using the SwissTargetPrediction database.

Target Gene Screening

AR-related target genes were retrieved from the GeneCards database (https://www.genecards.org/) using the keywords “allergic rhinitis” and “nasosinusitis.” On the Venn2.1.0 platform (http://bioinfogp.cnb.csic.es/tools/venny/index.html), the compound targets of Mahuang Xixin Fuzi Decoction and disease targets were analyzed, and the intersection targets were screened, which represent the potential targets through which Mahuang Xixin Fuzi Decoction may act on AR. Statistical analysis of the intersection targets was performed using Excel, and a Venn diagram was generated. A “herb–active component–potential target” network was constructed using Cytoscape 3.10.0, followed by topological analysis to screen core components.

Construction of Protein–Protein Interaction Network

The intersection targets were imported into the String database (https://string-db.org/) with a confidence score >0.4 and species set to “Homo sapiens” to obtain PPI relationships. The PPI network was constructed using Cytoscape 3.10.1, and topological analysis was performed to identify core targets based on degree centrality and centrality values.

Enrichment Analysis

The DAVID database was utilized to perform Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on the core targets. The enrichment results were visualized using the Microbioinformatics platform. The GO analysis encompassed three aspects: biological process (BP), cellular component (CC), and molecular function (MF).

Molecular Docking Validation

To validate the binding activity between the active components of Mahuang Xixin Fuzi Decoction and the core targets, the protein structures of the core targets were downloaded from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB, https://www.rcsb.org/) database. The proteins were preprocessed using PyMOL 3.7.9 software. The core components were processed using AutoDock Tools 1.5.7 software, including hydrogen addition, torsion bond setting, and automatic charge assignment. After setting the docking box, virtual molecular docking was performed. The results were visualized using PyMOL 3.7.9 software.

Results

Main Components and Targets of Mahuang Xixin Fuzi Decoction

A total of 27 active components of Mahuang Xixin Fuzi Decoction were retrieved from the TCMSP database, as shown in [Table 1]. The SwissTargetPrediction database was used to screen targets with a probability greater than zero for the 27 compounds. After deduplication, 506 potential targets were obtained.

Screening of Allergic Rhinitis Targets and Identification of Intersection Targets

AR-related targets were retrieved and screened from the GeneCards database, yielding 2,447 disease targets after deduplication. The intersection between the compound targets of Mahuang Xixin Fuzi Decoction and the AR-related targets was analyzed using the Venn2.1.0 platform, resulting in 165 common targets, which represent the potential targets of Mahuang Xixin Fuzi Decoction for AR treatment. A Venn diagram was generated, as shown in [Fig. 1]. A “herb–active component–potential target” network was constructed using Cytoscape 3.10.0 software and subjected to topological analysis, as shown in [Fig. 2]. The active components were ranked by degree value in descending order. The top five active components were naringenin, genkwanin, deoxyandrographolide, karakoline, and karanjin, suggesting that these five components may be the key effective components of Mahuang Xixin Fuzi Decoction for treating AR and could serve as Q-markers for formulation analysis.

Protein–Protein Interaction Network Analysis

The potential targets were subjected to PPI network analysis using the String database and visualized with Cytoscape 3.10.0 software ([Fig. 3]). In the network, nodes represent potential targets, and edges represent the correlation between proteins. Topological analysis of the PPI network was performed using the CytoNCA plugin to obtain metrics such as degree centrality, betweenness centrality, and closeness centrality. A total of 32 targets with values above the mean for these three metrics were identified as core targets ([Fig. 4]). Targets with higher degree values play more critical roles in protein interactions and are likely involved in essential biological processes. The top five targets ranked by degree value were protein kinase B1 (PKB1/AKT1), SRC, signal transducer and activator of transcription 3 (STAT3), prostaglandin-endoperoxide synthase 2 (PTGS2), and epidermal growth factor receptor (EGFR). These five targets are proposed as key therapeutic targets of Mahuang Xixin Fuzi Decoction for AR ([Table 2]).

Enrichment Analysis Results

GO enrichment analysis yielded a total of 834 functional items, including 618 BPs, 72 CCs, and 144 MFs. The top 10 ranked BPs, CCs, and MFs were visualized, and a bar chart was drawn. The top 10 terms for BPs, CCs, and MFs were visualized as bar plots ([Fig. 5]). Key BPs included phosphorylation, inflammatory response, protein phosphorylation, response to xenobiotic stimulus, etc.; CC terms were enriched in plasma membrane, cell surface, synapse, dendrite, etc.; MF terms included ATP-binding, identical protein-binding, protein kinase activity, and protein tyrosine kinase activity, etc.

KEGG pathway analysis identified 165 pathways (p < 0.05). The top 20 pathways were plotted as a bubble chart ([Fig. 6]), where redder/larger bubbles indicate higher significance. Key pathways implicated in AR treatment were the calcium signaling pathway, EGFR tyrosine kinase inhibitor resistance, hypoxia-inducible factor-1 (HIF-1) signaling pathway, endocrine resistance, and inflammatory mediator regulation of transient receptor potential (TRP) channels, etc.

Molecular Docking Validation

As demonstrated by Lu et al.,[13] binding energy <0 kcal·mol⁻¹ indicates spontaneous binding, while less than −5.0 kcal·mol⁻¹ suggests strong binding. Molecular docking of core targets (AKT1, STAT3, PTGS2) with naringenin, genkwanin, deoxyandrographolide, karakoline, and karanjin revealed binding energies less than −5 kcal·mol⁻¹ ([Table 3]), which confirms stable interactions. These components are proposed as Q-markers for the decoction's anti-AR efficacy. Docking visualizations are shown in [Figs. 7] [8] [9] [10] [11].

Discussion

This study identified core targets such as AKT1, SRC, STAT3, PTGS2, and EGFR through PPI network construction and analysis, suggesting that these targets are closely related to the mechanism of Mahuang Xixin Fuzi Decoction in treating AR. The “herb–active component–potential target” network analysis indicated that the core active components of this formula for AR treatment may include naringenin, genkwanin, deoxyandrographolide, karakoline, and karanjin. Molecular docking revealed strong binding between these active components and the core targets, implying that these components could serve as potential Q-markers for the decoction in AR treatment. However, comprehensive pharmacodynamic markers for this formula still require further in-depth research combined with clinical applications.

The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway is involved in various biological functions such as cell proliferation and differentiation. Activated AKT enhances the degradation of IκB kinase, leading to the activation of nuclear factor-κB (NF-κB).[14] Activated NF-κB can induce the expression of inflammatory cytokines and chemokines, promoting the infiltration and aggregation of inflammatory cells at the site of inflammation and accelerating inflammatory progression.[15] SRC, a member of the non-receptor tyrosine kinase family, can activate multiple signaling pathways, such as NF-κB and mitogen-activated protein kinase (MAPK), to promote the release of inflammatory factors and regulate the migration and activation of immune cells. STAT3, a critical transcriptional factor, enhances the expression of inflammation-related genes (e.g., IL-6, TNF-α) upon activation, influencing Th17 cell differentiation and thereby exacerbating or alleviating allergic inflammatory responses. Studies have shown that STAT3 inhibitors can suppress the accumulation of Th2 and Th17 cells in the airways of asthmatic mice and reduce goblet cell hyperplasia in epithelial tissues, which ameliorates inflammation.[16] Other research indicates that IL-37 can mitigate allergic reactions in AR mice by downregulating the IL-4/STAT6 and IL-6/STAT3 pathways.[17] PTGS2, also known as COX-2, is a key inflammation-related enzyme highly expressed at inflammatory sites. It catalyzes the conversion of arachidonic acid to prostaglandin H2 (PGH2), which is further metabolized into PGE2. PGE2 promotes inflammatory responses, including vasodilation and leukocyte infiltration, by activating cell surface receptors EP1–EP4.[18] Additionally, PGE2 suppresses anti-inflammatory responses by activating vascular endothelial growth factor (VEGF) expression and inhibiting the activity of T cells and natural killer cells.[19] [20] EGFR, the epidermal growth factor receptor, plays a pivotal role in inflammatory signal transduction, epithelial cell proliferation, and mucus secretion, all of which are closely associated with the pathogenesis of AR. Studies demonstrate that inhibiting EGFR and PTGS2 expression effectively alleviates rhinitis symptoms.[21] In summary, targets such as AKT1, SRC, STAT3, PTGS2, and EGFR regulate the proliferation, migration, and activation of inflammatory cells, as well as the synthesis of inflammatory mediators, which play a critical role in the pathogenesis of AR. These targets may represent key therapeutic points for Mahuang Xixin Fuzi Decoction in AR treatment.

GO enrichment analysis revealed that the potential protein targets are primarily involved in biological processes such as protein phosphorylation, inflammatory responses, and responses to exogenous stimuli. These targets are associated with signaling pathways, including the calcium signaling pathway, EGFR tyrosine kinase inhibitor resistance, HIF-1 signaling pathway, endocrine resistance, and inflammatory mediator regulation of TRP channels. Furthermore, molecular docking results confirmed strong binding affinity between the core active components and key target proteins (e.g., AKT1, STAT3, PTGS2).

Conclusions

This study systematically elucidated the potential mechanism of Mahuang Xixin Fuzi Decoction in treating AR using network pharmacology and molecular docking, and highlighted the formula's holistic regulatory characteristics of “multicomponent, multitarget, multipathway.” Multiple chemical components in Mahuang Xixin Fuzi Decoction may ameliorate AR by regulating diverse targets and biological processes. Naringenin, genkwanin, and deoxyandrographolide are proposed as potential Q-markers for this decoction in AR treatment. These findings align with the holistic perspective and syndrome differentiation principles in TCM. The study provides a theoretical foundation for exploring the pharmacodynamic material basis of this formula and further mechanism research, and also offers novel approaches for the modern study of Chinese herbal compounds.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Lingli Cao: Project administration, data curation, formal analysis, and writing -original draft. Xiaomin Chen: Writing-review and editing. Yun Guo: Writing-review and editing. Yinman Feng: Project administration and funding acquisition.

• References

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Address for correspondence

Publication History

Received: 22 January 2025

Accepted: 25 March 2025

Article published online:
27 June 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References

• 1 Kong Q, Cong LN. Efficacy of the Mahuang Fuzi Xixin decoction on bronchopneumoniain children. Clin J Chin Med 2019; 11 (34) 74-76
  Search in Google Scholar
• 2 Zhang XX, Lyu XD, Pang LJ. et al. Efficacy evaluation of Modified Mahuang Fuzi Xixin Decoction in the treatment of adult asthma. Liaoning Zhongyiyao Daxue Xuebao 2020; 22 (09) 126-131
  Search in Google Scholar
• 3 Wang TJ, Yu RZ, Liu YM. Brief analysis of Mahuang Fuzi Xixin Decoction in treating lung collateral disease. Zhonghua Zhongyiyao Xuekan 2023; 41 (10) 38-40
  Search in Google Scholar
• 4 Cui HQ. Effects of Modified Guizhi Decoction without Shaoyao but with Mahuang, Xixin and Fuzi Decoction on neurological function in patients with cerebral infarction. Henan Tradit Chin Med 2020; 40 (10) 1507-1510
  Search in Google Scholar
• 5 Cai Q, Qian L. Summary of clinical experience in treating sick sinus syndrome with Mahuang Fuzi Xixin Decoction. Gansu Med J 2019; 38 (11) 987-989
  Search in Google Scholar
• 6 Nie YX, Xie HB, Wang LX. et al. Experience of Xie Haibo in treating bradyarrhythmia with Mahuang Fuzi Xixin Decoction. Asia-Pacific Tradit Med 2023; 19 (04) 97-99
  Search in Google Scholar
• 7 Zhan CS. Clinical efficacy of modified Mahuang Fuzi Xixin Decoction in treating chronic arrhythmia. Linchuang Heli Yongyao Zazhi 2022; 15 (34) 38-41
  Search in Google Scholar
• 8 Zhang SJ, Wang XR, Li XY. et al. Empirical cases of Mahuang Fuzi Xixin Decoction in treating yang deficiency and cold coagulation disease. Chin J Ethnomed Ethnopharm 2023; 32 (21) 88-90
  Search in Google Scholar
• 9 Gao YG. Clinical observation of Lizhong Decoction combined with Mahuang Fuzi Xixin Decoction in the treatment of acute allergic rhinitis due to deficiency-cold. Chin Med Digest (Otorhinolaryngol) 2023; 38 (04) 53-55
  Search in Google Scholar
• 10 Xing YW, Zhang YX, Li Y. et al. Chen Shouqiang's clinical experience in treating allergic rhinitis with fusion acupuncture combined with Mahuang Xixin Fuzi Decoction. Guid J Tradit Chin Med Pharm 2024; 30 (03) 164-167
  Search in Google Scholar
• 11 Li L, Su K. Professor Chen Xue Zhong's experience in treating allergic diseases with Modified Mahuang Fuzi Xixin Decoction. Guangxi Zhongyiyao 2021; 44 (02) 42-44
  Search in Google Scholar
• 12 Liu SY, Wang SP. Effects of Mahuang Xixin Fuzi Decoction on INF-γ and IL-13 levels in rats with allergic rhinitis. Henan Tradit Chin Med 2017; 37 (08) 13
  Search in Google Scholar
• 13 Lu XP, Xu L, Meng LW, Wang LL, Niu J, Wang JJ. Divergent molecular evolution in glutathione S-transferase conferring malathion resistance in the oriental fruit fly, Bactrocera dorsalis (Hendel). Chemosphere 2020; 242: 125203
  PubMedSearch in Google Scholar
• 14 Jing SS, Zhang FY, Wang RZ. Research progress on the treatment of allergic rhinitis by traditional Chinese medicine through regulating mitochondrial quality control. Guid J Tradit Chin Med Pharm 2025; 31 (03) 155-162
  Search in Google Scholar
• 15 Li M, Li W, Xia YF. et al. Protective effect of compound glycyrrhizin on lung injury in mice with viral pneumonia via the PI3K/Akt/NF-κB Pathway. Zhongchengyao 2023; 45 (11) 3775-3779
  Search in Google Scholar
• 16 Gavino AC, Nahmod K, Bharadwaj U, Makedonas G, Tweardy DJ. STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model. Allergy 2016; 71 (12) 1684-1692
  PubMedSearch in Google Scholar
• 17 Wang J, Shen Y, Li C. et al. IL-37 attenuates allergic process via STAT6/STAT3 pathways in murine allergic rhinitis. Int Immunopharmacol 2019; 69: 27-33
  PubMedSearch in Google Scholar
• 18 Xiao X, Kang LP, Dai D. et al. Mechanism of Kai Xuan Jie Du Core Formula in improving skin lesions of psoriasis model mice by regulating PTGS2. Chin J Exp Tradit Med Formul 2025; 5: 1-19
  CrossrefSearch in Google Scholar
• 19 Huang R, Yu J, Zhang B, Li X, Liu H, Wang Y. Emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and treatment. Biomaterials 2025; 315: 122954
  PubMedSearch in Google Scholar
• 20 Morotti M, Grimm AJ, Hope HC. et al. PGE₂ inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature 2024; 629 (8011) 426-434
  PubMedSearch in Google Scholar
• 21 Liu XY. Network Pharmacology-based Approach for Investigating the Pharmacological Mechanism of Xanthii Fructus Active Ingredients in Treatment of Allergic. Qingdao: Qingdao University; 2023
  Search in Google Scholar