Network Pharmacology and Molecular Docking Analysis of Fuzheng Gankang Pill in Treating Combined Allergic Rhinitis and Asthma Syndrome with Lung–Spleen Qi Deficiency and Wind–Cold Invading the Lung Syndrome

Abstract

Objective

To elucidate the mechanism of Fuzheng Gankang Pill in treating combined allergic rhinitis and asthma syndrome (CARAS) with lung–spleen qi deficiency and wind–cold invading the lung syndrome using network pharmacology and molecular docking.

Methods

The active components and targets of the 13 herbs in Fuzheng Gankang Pill were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and HERB. A “core herb-active component–target” network was constructed using Cytoscape to screen core components. CARAS disease targets were obtained from Genecards, National Center for Biotechnology Information (NCBI), and Online Mendelian Inheritance in Man (OMIM). Targets related to the clinical phenotypes of CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome were retrieved from the Traditional Chinese Medicine Syndrome Ontology and Multidimensional Quantitative Association Calculation Platform. The intersection of CARAS disease targets and syndrome-related targets yielded CARAS disease–syndrome targets. The intersection of Fuzheng Gankang Pill component-related targets and CARAS disease–syndrome targets provided “disease–syndrome–formula” intersection targets. These targets were uploaded to the STRING database for protein–protein interaction (PPI) network analysis, with topological analysis identifying key targets. Metascape was used for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Molecular docking validation was performed using AutoDock Vina 1.1.2.

Results

The 13 core herbs of Fuzheng Gankang Pill contain a total of 200 active ingredients and 289 related targets. There are 2,412 disease targets for CARAS and 735 corresponding disease targets for the main and secondary symptoms of lung–spleen qi deficiency and wind–cold invading the lung. Through the Venn diagram, a total of 35 intersecting targets were obtained for Fuzheng Gankang Pill, CARAS, and the combination of lung–spleen qi deficiency and wind–cold invading the lung syndrome. Quercetin, Polygonatum sibiricum flavonoids, β-sitosterol, baicalein, kaempferol, etc., are core components. PPI network analysis found that tumor necrosis factor (TNF), prostaglandin-endoperoxide synthase 2 (PTGS2), interleukin (IL)-1β, IL-6, transforming growth factor beta 1 (TGFβ1), BCL2, etc., are the core targets for the compound to exert therapeutic effects. GO enrichment analysis showed that the 13 core drugs of Fuzheng Gankang Pill mainly participate in key biological processes such as positive regulation of protein modification, response to hormones, and negative regulation of cell population proliferation through protein kinases in areas such as membrane rafts, membrane microregions, plasma membrane protein complexes, and receptor complexes. KEGG enriched a total of 30 signaling pathways. Molecular docking shows that active ingredients such as quercetin and kaempferol bind stably to TNF (binding energy ≤ −9.0 kcal·mol⁻¹) and PTGS2 (≤ −8.5 kcal·mol⁻¹).

Conclusion

Fuzheng Gankang Pill may regulate biological processes such as cell apoptosis, tissue remodeling, inflammatory response, and immune response by acting on core targets such as TNF and PTGS2 through its core components quercetin, baicalein, β-sitosterol, baicalein, and kaempferol, thereby exerting therapeutic effects on CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome.

 

MissingLinkText

Keywords

Fuzheng Gankang Pill - CARAS - lung–spleen qi deficiency - wind–cold invading the lung syndrome - network pharmacology - molecular docking

Introduction

Combined allergic rhinitis and asthma syndrome (CARAS) is a respiratory disease characterized by the simultaneous occurrence of clinical or subclinical allergic symptoms in both the upper respiratory tract (allergic rhinitis) and lower respiratory tract (asthma).[1] Although allergic rhinitis and asthma are typically diagnosed and treated separately, many patients actually suffer from both conditions simultaneously. Studies show that over 70% of asthma patients also have allergic rhinitis,[2] while more than 47% of allergic rhinitis patients have asthma.[3] These can be considered as manifestations of the same disease or syndrome in different locations. Currently, Western medicine primarily treats CARAS by controlling symptoms and alleviating the condition through medication, but it cannot achieve a cure. Long-term medication brings high economic costs and often fails to achieve ideal preventive effects.[4] [5] Commonly used drugs such as glucocorticoids, bronchodilators, and antihistamines can alleviate symptoms to some extent, but the condition tends to relapse after discontinuation, and prolonged use can lead to drug tolerance.[6] The pathogenesis of CARAS involves diverse allergens, varied immune responses, complex interactions between genetic and environmental factors, and intricate pathophysiological mechanisms.[7] Therefore, personalized treatment plans tailored to individual patients are needed. However, current approaches like allergen-specific immunotherapy have single drug targets, lack personalization, and often come with significant side effects.[8] Traditional Chinese medicine (TCM), with its multicomponent synergistic effects, multitarget comprehensive treatment, minimal side effects, absence of drug resistance,[9] and holistic regulation of bodily functions, offers significant advantages in treating CARAS.[10] TCM not only alleviates symptoms but also emphasizes overall bodily regulation, which aligns with the inevitable demands of modern medical development.[11] Extensive research demonstrates the important social benefits of TCM in preventing and treating CARAS.[12] When healthy qi is strong inside, pathogenic qi cannot interfere. From the perspective of TCM, the pathogenesis of CARAS is often related to dysfunction of the lung, spleen, kidney, and other zang-fu organs. The disease mechanism involves two aspects: external pathogen invasion and internal visceral deficiency.[13] Among various syndromes, the lung–spleen qi deficiency with wind–cold invading the lung syndrome has unique pathological manifestations, with its pathological factors revolving around “wind” “phlegm,” and “deficiency.” The fundamental pathogenesis is “latent phlegm internally stored, triggered by external pathogens, leading to disease onset.”[14] Wind–cold pathogen is significant external factor inducing CARAS. When the body is overworked, exposed to wind while sweating, or subjected to sudden climate changes, wind–cold pathogen invades the body surface, first attacking the lung.[15] The lung is delicate organ intolerant of cold and heat; when wind–cold pathogen constrict the surface, lung qi fails to disperse. In autumn and winter, wind–cold pathogen easily invade the body through the nose, mouth, or skin pores, and lodge in the lung. The spleen, as the foundation of postnatal life and the source of qi and blood, governs the transportation and transformation of nutrients. In the pathogenesis of CARAS, lung–spleen qi deficiency is a critical internal factor.[16] When lung and spleen qi is deficient, the body's ability to resist external pathogens declines. Lung deficiency leads to weakened defensive qi, which makes the skin pores loose and vulnerable to external pathogen invasion. Spleen deficiency disrupts transportation and transformation, impairs the distribution of nutrients and the production of qi and blood, and further weakens lung function due to insufficient nourishment. From a modern medical perspective, cold stimulation may cause vasoconstriction in the nasal and airway mucosa and reduce mucosal barrier function.[17] Cold stimulation can also alter the body's neuroendocrine regulatory mechanisms by affecting airway epithelial cell function, airway smooth muscle contraction, and airway inflammatory responses, thus increasing airway reactivity.[18] Under cold stimulation, the body is more prone to allergic reactions upon exposure to allergens. Patients with lung–spleen qi deficiency often exhibit weakened immune function. The immune system acts as the body's defense mechanism. When lung and spleen functions are impaired, the activity and quantity of immune cells, as well as the production of immunoglobulins, are affected, which will reduce the body's ability to recognize and eliminate allergens effectively. This increases sensitivity to allergens[19] and makes CARAS more likely to occur. Wind–cold invading the lung and lung–spleen qi deficiency play pivotal roles in the pathogenesis of CARAS. External pathogens first attack the lung. Once the disease manifests, due to insufficient healthy qi, the condition tends to recur. Although symptoms may temporarily improve after treatment, the underlying lung–spleen qi deficiency remains unaddressed, making relapse likely upon reexposure to allergens or climate changes. Moreover, the human body is an integrated whole. Prolonged lung–spleen qi deficiency may affect other organs, such as the kidneys impairing its qi-receiving function and exacerbating symptoms like shortness of breath and wheezing.[20] The classic formula Yuhan Decoction from Dongyuan Li's Secrets from the Orchid Chamber (Lanshi Micang) has shown remarkable efficacy in treating lung diseases characterized by lung–spleen qi deficiency with wind–cold invading the lung syndrome.[21] Based on Yuhan Decoction, Professor Mingli Zhang developed Fuzheng Gankang Pill, which has been widely used in clinical practice to treat CARAS with good results. Fuzheng Gankang Pill is a traditional Chinese medicine compound composed of 13 herbs: Huangqi (Scutellariae Radix), Dangshen (Codonopsis Radix), Cangzhu (Atractylodis Rhizoma), Baizhi (Angelicae Dahuricae Radix), Fangfeng (Saposhnikoviae Radix), Huangqin (Scutellariae Radix), Shengma (Cimifugae Rhizoma), Gancao (Glycyrrhizae Radix et Rhizoma), Kuandonghua (Farfarae Flos), Qianghuo (Notopterygii Rhizoma et Radix), Chenpi (Citri Reticulatae Pericarpium), Xinyi (Magnoliae Flos), Huanglian (Coptidis Rhizoma). It is mainly used to treat cold qi and wind evil, which can damage the fur and cause nasal congestion, coughing, and wheezing. However, the mechanism of Fuzheng Gankang Pill in treating CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome has not been fully elucidated. Therefore, this study employs network pharmacology and molecular docking to clarify the potential molecular mechanisms of Fuzheng Gankang Pill in treating this syndrome. By systematically integrating the active components of the formula, their targets, and key information related to the disease and syndrome, such as genes and signaling pathways, this study aims to predict the multitarget, multipathway mechanisms of the formula. The findings may provide guidance for precise medication in clinical practice, optimize treatment strategies, and improve patient recovery outcomes.

 

MissingLinkText

Methods

Screening of Active Components in Fuzheng Gankang Pill and Acquisition of Corresponding Gene Targets

The active components of the core herbs in Fuzheng Gankang Pill consisting of Huangqi (Scutellariae Radix), Dangshen (Codonopsis Radix), Cangzhu (Atractylodis Rhizoma), Baizhi (Angelicae Dahuricae Radix), Fangfeng (Saposhnikoviae Radix), Huangqin (Scutellariae Radix), Shengma (Cimifugae Rhizoma), Gancao (Glycyrrhizae Radix et Rhizoma), Kuandonghua (Farfarae Flos), Qianghuo (Notopterygii Rhizoma et Radix), Chenpi (Citri Reticulatae Pericarpium), Xinyi (Magnoliae Flos), Huanglian (Coptidis Rhizoma) were searched using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP: http://tcmspw.com/tcmsp.php) and HERB (http://herb.ac.cn/). The screening criteria for active components were oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18. After merging and deduplicating the screened active components, the related targets were identified based on TCMSP and corrected using the UniProt database (https://www.uniprot.org). The core herbs, active components, and corresponding targets were imported into Cytoscape software to construct a “core herb-active component–target” network for Fuzheng Gankang Pill, and topological analysis was performed to screen core components.

 

MissingLinkText

Acquisition of Disease–Syndrome Targets and Intersection Targets with Active Components of Fuzheng Gankang Pill

The targets related to CARAS, allergic rhinitis, and asthma were retrieved from the Genecards database (https://www.genecards.org), the National Center for Biotechnology Information (NCBI) database (https://www.ncbi.nlm.nih.gov/), and the Online Mendelian Inheritance in Man (OMIM) database (https://www.omim.org/). Duplicate genes from each database were removed to obtain the final CARAS disease-related genes.

Based on the main clinical phenotypes of CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome (including nasal congestion, clear nasal discharge, spontaneous sweating, sneezing, cough, wheezing, and chest tightness), the syndrome-related targets were retrieved from the Traditional Chinese Medicine Syndrome Ontology and Multidimensional Quantitative Association Computing Platform (SoFDA: http://www.tcmip.cn/syndrome/front/). The intersection of CARAS disease-related targets and syndrome-related targets was taken to obtain CARAS disease–syndrome targets. The intersection of Fuzheng Gankang Pill active component-related targets and CARAS disease–syndrome targets was then taken to obtain “disease–syndrome–formula” intersection targets.

 

MissingLinkText

Protein–Protein Interaction Network Analysis and Screening of Key Targets

The “disease–syndrome–formula” intersection targets were uploaded to the STRING database (https://string-db.org/) for protein–protein interaction (PPI) analysis, with the species set as “Homo sapiens.” The PPI network data file was downloaded and imported into Cytoscape software for further analysis and screening to identify key targets.

 

MissingLinkText

Enrichment Analysis

Gene enrichment analysis is a method for analyzing gene expression information. Enrichment refers to the process of filtering and screening gene functional nodes based on genomic annotation information. After classification, it helps determine whether genes share commonalities in aspects such as function or composition.

The Metascape online analysis system (http://metascape.org/gp/index.html) was used for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. GO analysis mainly includes three aspects: cellular component (CC), molecular function (MF), and biological process (BP).

 

MissingLinkText

Molecular Docking Validation

The 3D structures of component molecules were downloaded in SDF format from the PubChem database based on their CAS numbers. The structures were imported into ChemBio3D Ultra 14.0 for energy minimization, with the Minimum RMS Gradient set to 0.0001, and saved in mol2 format. The optimized small molecules were imported into AutoDockTools 1.5.6 for hydrogen addition, charge calculation, charge assignment, and rotatable bond setting, then saved in “pdbqt” format. The PDB IDs of key targets were downloaded from the PDB database. The protein structures were imported into PyMOL 2.3.0 to remove crystallized water and original ligands. The protein structures were then imported into AutoDockTools for hydrogen addition, charge calculation, charge assignment, and atom type designation, and saved in pdbqt format. The binding sites of proteins were predicted using POCASA 1.1, and molecular docking was performed using AutoDock Vina 1.1.2.

 

MissingLinkText

 

MissingLinkText

Results

Active Components and Corresponding Targets of Fuzheng Gankang Pill

The 13 main herbs in Fuzheng Gankang Pill contained a total of 264 active components, including 17 from Huangqi (Scutellariae Radix), 17 from Dangshen (Codonopsis Radix), 4 from Cangzhu (Atractylodis Rhizoma), 20 from Baizhi (Angelicae Dahuricae Radix), 18 from Fangfeng (Saposhnikoviae Radix), 32 from Huangqin (Scutellariae Radix), 8 from Shengma (Cimifugae Rhizoma), 88 from Gancao (Glycyrrhizae Radix et Rhizoma), 16 from Kuandonghua (Farfarae Flos), 13 from Qianghuo (Notopterygii Rhizoma et Radix), 5 from Chenpi (Citri Reticulatae Pericarpium), 15 from Xinyi (Magnoliae Flos), and 11 from Huanglian (Coptidis Rhizoma). After screening and deduplication, 200 active components were obtained. The related targets of these active components were acquired from TCMSP and standardized using UniProt, yielding 289 targets such as PTGS2, NCOA2, CALM1, AR, PTGS1, HSP90AA1, ESR1, SCN5A, NOS2, and PRSS1. The data of the 13 core herbs of Huangqi (Scutellariae Radix), Dangshen (Codonopsis Radix), Cangzhu (Atractylodis Rhizoma), etc., 200 active components, and 289 related targets were organized to construct the “core herb-active component–target” network of Fuzheng Gankang Pill ([Fig. 1]). In this network, core herbs, active components, and targets are represented by green ellipses, colored hexagons, and yellow diamonds, respectively, with gray lines indicating corresponding relationships. The network reveals overlapping active components among the herbs, and these overlapping components are often associated with more gene targets, suggesting that quercetin, luteolin, β-sitosterol, wogonin, and kaempferol may be the core components responsible for the therapeutic effects of Fuzheng Gankang Pill.

Fig. 1 “Core herb-active component–target” network of Fuzheng Gankang Pill.

 

MissingLinkText

Disease–Syndrome Targets and Intersection Targets with Active Components of Fuzheng Gankang Pill

Targets related to CARAS, allergic rhinitis, and asthma were retrieved from multiple databases, including Genecards, NCBI, and OMIM. After removing duplicates, 2 412 disease targets were obtained. Additionally, 735 targets corresponding to the main and secondary symptoms of lung–spleen qi deficiency with wind–cold invading the lung syndrome were retrieved from the SoFDA platform. A Venn diagram was used to identify the intersection targets among the active components of Fuzheng Gankang Pill, CARAS disease targets, and syndrome targets, which yielded 35 “disease–syndrome–formula” intersection targets ([Fig. 2]).

Fig. 2 Venn diagram of intersection targets.

A network was constructed using the intersection targets of the active components of Fuzheng Gankang Pill and CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome ([Fig. 3]). In this network, the left side features green elliptical nodes representing core herbs, with outer nodes representing corresponding active components. The right side includes arrow-shaped nodes representing disease–syndrome nodes and yellow quadrilateral nodes representing the “disease–syndrome–formula” intersection targets.

Fig. 3 Network of Fuzheng Gankang Pill active components and “disease–syndrome–formula” intersection targets.

 

MissingLinkText

Protein–Protein Interaction Network Analysis of “Disease–Syndrome–Formula” Intersection Targets

The intersection targets were imported into STRING for PPI analysis and visualized using Cytoscape. The PPI network consisted of 35 nodes and 319 edges. Topological analysis in Cytoscape revealed an average node degree of 18.2, a median degree of 21, and an average local clustering coefficient of 0.816. Ten targets with degree values ≥ 26 were identified: interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), TGF-β1, PTGS2, BCL2, STAT3, TP53, EGFR, and PPARG. These core targets are likely to play key roles in the therapeutic mechanism of Fuzheng Gankang Pill for CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome. The nodes were sized according to their degree values and arranged in concentric circles ([Fig. 4]).

Fig. 4 Multicircle diagram of PPI network analysis for intersection targets. PPI, protein–protein interaction.

 

MissingLinkText

Enrichment Analysis

GO and KEGG enrichment analyses of the intersection targets were performed using Metascape. The results showed that: CC enriched in membrane raft, membrane microdomain, plasma membrane protein complex, receptor complex, neuronal cell body, cell body, and dendrite, etc.; MF enriched in protein kinase regulator activity, protein kinase binding, protein phosphatase binding, transcription factor binding, cytokine receptor binding, and signaling receptor regulator activity, etc.; BP enriched in positive regulation of protein modification process, response to hormone, positive regulation of protein phosphorylation, regulation of smooth muscle cell proliferation, gland development, positive regulation of programmed cell death, positive regulation of miRNA metabolic process, cellular response to organic cyclic compound, and regulation of miRNA metabolic process, etc.([Fig. 5]). KEGG enrichment identified pathways such as cancer-related pathways, FoxO signaling pathway, AGE-RAGE signaling pathway in diabetic complications, human papillomavirus infection, JAK-STAT signaling pathway, and melanoma, etc. The top 30 pathways ranked by p-value were visualized ([Fig. 6]).

Fig. 5 Bar chart of GO enrichment analysis. GO, Gene Ontology.

Fig. 6 Bubble chart of KEGG signaling pathways. KEGG, Kyoto Encyclopedia of Genes and Genomes.

 

MissingLinkText

Molecular Docking

The core targets from the PPI network—IL-6, TNF, BCL2, EGFR, IL-1β, PPARG, PTGS2, STAT3, TGF-β1, and TP53—were selected as receptors. Six core components with high degree values—quercetin, luteolin, β-sitosterol, wogonin, and kaempferol—were chosen as small molecule ligands. Molecular docking validation was performed using AutoDock Vina 1.1.2, and the binding energy matrix is shown in [Fig. 7]. Lower binding energy indicates more stable molecular docking: binding energy <0 kcal·mol⁻¹ suggests binding activity, < − 7 kcal·mol⁻¹ indicates good binding activity, and < − 9 kcal·mol⁻¹ signifies very strong binding activity. The binding energy matrix revealed favorable binding between the active components of Fuzheng Gankang Pill and the core targets, with TNF and PTGS2 exhibiting low binding energy with all small molecules. The docking modes of TNF and PTGS2 with the small molecule ligands were visualized using Pymol 2.3.0 ([Fig. 8]). The specific energy values are shown in [Table 1].

Fig. 7 Thermal map of binding energy matrix between active components and core targets.

Fig. 8 Docking diagrams of core components of Fuzheng Gankang Pill with TNF and PTGS2. PTGS2, prostaglandin-endoperoxide synthase 2; TNF, tumor necrosis factor.

Table 1 Molecular docking energy values (kcal·mol⁻¹)

Core component	IL-6	TNF	BCL2	EGFR	IL-1β	PPARG	PTGS2	STAT3	TGF-β1	TP53
β-sitosterol	−6.7	−9.2	−7.6	−7.3	−6.9	−7.9	−7.2	−7.2	−5.9	−6.5
kaempferol	−6.5	−8.8	−6.8	−7.7	−6.3	−7.1	−9	−7.2	−6.7	−6.6
luteolin	−7.2	−9	−7	−7.7	−6.8	−7.6	−9.8	−7.6	−6.7	−7.2
quercetin	−7.1	−9.1	−7	−7.9	−6.9	−7.5	−9.9	−7.4	−6.9	−6.9

 

MissingLinkText

 

MissingLinkText

Discussion

The production of large amounts of cytokines during inflammatory responses is a central link in the pathogenesis of CARAS.[22] Under the influence of endopeptidases and the mitogen-activated protein kinase (MAPK) signaling pathway, inflammatory cells proliferate and activate, release toxic proteins and inflammatory mediators such as eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, and myelin basic protein (MBP). MBP can directly damage respiratory epithelial cells, compromise the integrity of the airway mucosa, thus making it more susceptible to allergens and other irritants.[23] When allergens invade the body, they bind to immunoglobulin E (IgE) on the surface of mast cells and basophils, which triggers degranulation and the release of inflammatory mediators such as histamine, prostaglandin D2, and cysteinyl leukotrienes.[24] Histamine causes vasodilation and increased permeability, leading to nasal mucosal congestion and edema, manifesting as symptoms like nasal itching and sneezing. Leukotrienes are potent bronchoconstrictors that promote mucus secretion and inflammatory cell chemotaxis, and it plays a critical role in asthma attacks.[25] Cytokines such as IL-4, IL-5, IL-13, and TNF also play key roles in the inflammatory response of CARAS. IL-4 promotes IgE production by B cells, IL-5 is essential for the growth, differentiation, and activation of eosinophils, and IL-13 stimulates mucus-secreting cell hyperplasia and increased mucus production and leads to airway obstruction. Thus, the infiltration of inflammatory cells and the release of inflammatory mediators are pivotal factors in the development of allergic respiratory symptoms.[26] In CARAS, inflammatory responses further activate immune cells, and this activation, in turn, feedbacks into immune system regulation.[27] The immune system not only defends against foreign pathogens like viruses, bacteria, and fungi but also maintains self-tolerance by recognizing and clearing abnormal cells, thereby preserving immune balance.[28] The pathogenesis of CARAS often involves an imbalance between Th1 and Th2 cells. Cytokines such as TNF-α secreted by Th2 cells play a critical role in inflammatory responses. Dendritic cells enhance their ability to uptake and process allergens in inflammatory environments, presenting antigenic information to T cells and modulating immune responses.[29] Persistent inflammatory responses can impair immune tolerance mechanisms, increase the body's sensitivity to allergens. Chronic inflammation and immune dysregulation lead to a sustained state of airway inflammation.[30] Chronic inflammation induces pathological changes such as nasal epithelial hyperplasia, goblet cell metaplasia, and submucosal fibrosis.[31] It also promotes airway remodeling, including bronchial wall thickening, smooth muscle hyperplasia, and mucus gland hypertrophy, which narrows the airway lumen, reduces wall elasticity, and exacerbates airflow limitation.[32] Inflammatory responses and immune dysregulation further drive the infiltration of inflammatory cells into surrounding tissues, and expand the scope of lesions.

CARAS is a complex allergic disease involving both the upper and lower respiratory tracts. Its pathogenesis intertwines immune imbalance, inflammatory responses, environmental factors, and is susceptible to genetic and infectious influences, which leads to recurrent symptoms. Additionally, significant individual variability and the lack of specific curative methods make it challenging to effectively control and cure the disease.[33] TCM integrates holistic concept and syndrome differentiation, employs a “constitution–disease–syndrome differentiation” diagnostic and therapeutic model. By holistically regulating the body's qi, blood, yin, and yang, as well as visceral functions, TCM aims to correct the patient's constitution (allergic predisposition), reinforce healthy qi and eliminate pathogens. This approach fundamentally improves the body's allergic state while reducing symptom recurrence and minimizing side effects.[34] Extensive clinical evidence demonstrates that integrated Chinese and Western medicine treatment for CARAS can rapidly alleviate symptoms while fundamentally adjusting the body's state, reducing disease relapse, mitigating the side effects and drug tolerance associated with Western medicine, and improving therapeutic outcomes.[35] In TCM, CARAS can be categorized under “Bi Qiu” (allergic rhinitis) and “Xiao Bing” (asthma).” Its etiology primarily involves two aspects: external pathogen invasion and visceral deficiency. The Huangdi's Inner Canon of Medicine (Huangdi Neijing) states: “When the flesh is not firm and the interstices are loose, wind disease easily arises.” Wind, the chief of the six excesses, often combines with cold, heat, or dampness to invade the body, serving as a key external factor in CARAS pathogenesis. When the body's healthy qi is insufficient and defensive qi is weak, wind pathogen readily takes advantage of this vulnerability to trigger disease. Invasion by wind–cold pathogen may impair lung qi diffusion, and cause nasal congestion, runny nose, and cough. Invasion by wind–heat pathogen tends to damage fluid and scorch the lung, force lung qi upward and result in nasal itching, yellow nasal discharge, fever, and wheezing. Lung, spleen, and kidney deficiency is the main manifestations of visceral impairment. “The lung governs qi, controls respiration, opens into the nose, and connects with the skin.” If lung qi is deficient, external pathogens easily invade and disrupt nasal and airway functions. As Basic State of Spirit in the Spiritual Pivot (Lingshu Benshen) notes: “When lung qi is deficient, the nose is obstructed and breathing is labored.” The lung regulates water pathways; qi deficiency affects fluid distribution and metabolism and causes water retention and phlegm formation. The spleen governs transportation and transformation. Spleen qi deficiency impairs these functions, leading to internal dampness accumulation that coalesces into phlegm. This phlegm may ascend to harass the lung, disrupt lung qi diffusion, and trigger allergic rhinitis and asthma. In the Discussion on the Most Important and Abstruse Theory of Plain Questions (Suwen Zhizhenyao Dalun) emphasizes: “All dampness, swelling, and fullness belong to the spleen,” highlighting the close relationship between spleen deficiency and dampness-related disorders. The kidney, as the foundation of innate constitution, governs qi reception. Kidney yang deficiency fails to warm the spleen earth, potentially causing spleen–kidney yang deficiency. This impairs qi transformation of fluid and leads to phlegm retention. If the kidney cannot receive qi, lung qi rebels upward and exacerbates asthma symptoms.

Fuzheng Gankang Pill is derived from modifications to Cold-Defensing Decoction, a classical formula from Dongyuan Li's Secrets from the Orchid Chamber (Lanshi Micang). Originally indicated for “cold and wind pathogen damaging the skin and hair, causing nasal obstruction and coughing with wheezing,” Professor Mingli Zhang skillfully applies this formula to treat allergic disorders like allergic rhinitis, asthma, and dermatitis. Although allergic rhinitis and asthma are distinct diseases, TCM recognizes their shared etiopathogenesis, permitting identical treatment based on the “different diseases, same treatment” principle—an approach remarkably consistent with modern medical understanding of allergic rhinitis with asthma. Considering CARAS patients' tendency for recurrence and chronicity, Professor Zhang developed Fuzheng Gankang Pill as a slow-acting pill formulation for long-term use. This modification facilitates gradual correction of deficiency, enhances pathogen resistance, prevents external invasions, and specifically treats lung–spleen qi deficiency with wind–cold invading the lung syndrome.

The prescription employs large doses of the vital qi-tonifying herbs Huangqi (Scutellariae Radix) and Dangshen (Codonopsis Radix) as sovereign medicines to address lung–spleen deficiency. The lung governs the skin and hair, whereas the spleen serves as the source of qi and blood generation. Huangqi (Scutellariae Radix) replenishes lung qi to strengthen the exterior and consolidate defensive qi and enhance the body's resistance to external pathogens. Its spleen-tonifying action ensures adequate production of qi and blood. As noted in Encountering the Sources of the Materia Medica (Ben Cao Feng Yuan): “Huangqi (Scutellariae Radix) can tonify deficiency of all five zang organs…clear lung heat…” When combined with Dangshen (Codonopsis Radix), these herbs synergistically reinforce both lung and spleen qi, substantially boosting the body's defensive capabilities, particularly benefiting those with constitutional qi deficiency. Five minister herbs, that is Cangzhu (Atractylodis Rhizoma), Baizhi (Angelicae Dahuricae Radix), Huangqin (Scutellariae Radix), Fangfeng (Saposhnikoviae Radix), and Shengma (Cimifugae Rhizoma), collectively exert effects to release the exterior, regulate the interior, awaken the spleen, and rectify qi. Cangzhu (Atractylodis Rhizoma) resolves external dampness while simultaneously strengthening the spleen and stomach, protecting healthy qi and ensuring complete elimination of cold–damp pathogen without lingering effects. Pouch of Pearls (Zhen Zhu Nang) describes it as “able to strengthen the stomach and calm the spleen—no other herb can eliminate swellings from dampness so effectively.” Compendium of Materia Medica (Bencao Gangmu) records: “Baizhi (Angelicae Dahuricae Radix), white in color and pungent in flavor, enters the hand Yangming channel; warm in nature and thick in property, it enters the foot Yangming channel; its aromatic ascending quality reaches the lung channel of hand Taiyin.” When combined with Cangzhu (Atractylodis Rhizoma), it enhances the effects of dispelling dampness, dispersing cold, releasing the exterior and unblocking the orifices. Treasury of Words on the Materia Medica (Bencao Huiyan) states: “Shengma (Cimifugae Rhizoma) is an agent that releases the exterior and raises yang.” It assists in elevating the body's yang qi, strengthening healthy qi's ability to resist pathogens while providing exterior-releasing properties useful for external contraction patterns. All herbs in the formula utilize the ascending nature of Shengma (Cimifugae Rhizoma) to reach affected areas. Treatise on the Spleen and Stomach (Pi Wei Lun) observes: “Without this guide, Renshen (Ginseng Radix et Rhizoma) and Huangqi (Scutellariae Radix) cannot ascend effectively.” Fangfeng (Saposhnikoviae Radix), known as “the moistening agent among wind herbs,” complements the sovereign herbs by boosting qi, securing the exterior, and expelling pathogens without damaging healthy qi or causing qi stagnation. Huangqin (Scutellariae Radix) prevents external pathogens from transforming into internal heat and dampness from turning to heat, while clearing lung–stomach heat. Combined with Cangzhu (Atractylodis Rhizoma), it enhances dampness–drying effects. While Huangqin (Scutellariae Radix) clears heat in the upper energizer, Huanglian (Coptidis Rhizoma) drains fire in the middle energizer—their combination powerfully clears heat, dries dampness, purges fire, and resolves toxicity. The paired use of Kuandonghua (Farfarae Flos) and Chenpi (Citri Reticulatae Pericarpium) facilitates lung qi diffusion and descent while transforming phlegm-dampness. Qianghuo (Notopterygii Rhizoma et Radix) releases the exterior and scatters cold while dispelling wind and overcoming dampness, whereas Xinyi (Magnoliae Flos) disperses wind cold and unblocks the nasal passages. These two herbs work synergistically, with one scattering and one unblocking, to dissipate wind–cold pathogen and restore nasal patency. Collectively, these herbs achieve the dual objectives of expelling pathogens and relieving the exterior while supporting healthy qi and consolidating the root.

Intersection analysis of formula targets with CARAS disease targets and lung–spleen qi deficiency with wind–cold invading lung syndrome targets revealed a comprehensive “formula–component–disease–syndrome–target” network. This demonstrated that key Fuzheng Gankang Pill components—quercetin, luteolin (LUT), β-sitosterol, wogonin, kaempferol, and stigmasterol—play principal therapeutic roles in CARAS with this syndrome pattern. Functioning as an integrated system, these components cooperatively exert anti-inflammatory, antioxidant, and immunomodulatory effects to maintain systemic equilibrium—perfectly aligning with TCM's holistic philosophy and syndrome differentiation principle. Quercetin directly binds glucose-6-phosphate dehydrogenase (G6PD), and competitively eliminate NADP binding in the catalytic domain to inhibit enzyme activity and exert antioxidant effects.[36] It also restricts overactivation of downstream PI3K/Akt and Ras/Raf/MEK/ERK pathways induced by oxidative stress and protects cells from excessive oxidative damage.[37] During inflammation, it suppresses production and release of inflammatory factors including TNF and IL-1.[38] LUT demonstrates antibacterial activity against Staphylococcus aureus and Listeria monocytogenes by disrupting cell membrane integrity and causing significant morphological changes. Additionally, it inhibits biofilm formation while enhancing antibiotic penetration to effectively eradicate single- and dual-species biofilm cells. Research indicates[39] LUT suppresses activation of nuclear factor kappa-B (NF-κB), JAK/STAT, and toll-like receptor (TLR) inflammatory signaling pathways, reducing release of IL-1β, IL-6, IL-8, IL-17, IL-22, TNF, and cyclooxygenase-2 (COX-2),[40] while promoting M2 macrophage polarization to inhibit inflammatory responses.[41] β-sitosterol exhibits anti-inflammatory and immunomodulatory properties.[42] In allergic asthma rat models, it significantly reduces Th17 cell proportions and proinflammatory cytokines (TNF-α, IL-4, IL-6, IL-17A) while increasing Treg cells and anti-inflammatory IL-35 levels, thereby correcting Th17/Treg imbalance.[43] Wogonin inhibits the RIPK1/RIPK3/MLKL signaling pathway in chronic obstructive pulmonary disease to alleviate airway inflammation.[44] It also reduces inflammatory factor production by suppressing silent information regulator 1-mediated high mobility group box-1 protein (HMGB1) deacetylation and NF-κB pathway activation, thereby mitigating inflammatory responses and apoptosis in acute lung injury,[45] [46] while effectively inhibiting pulmonary fibrosis progression in mycoplasma pneumonia.[47] Kaempferol alleviates pulmonary arterial hypertension development by regulating amino acid and arachidonic acid metabolism to inhibit abnormal autophagy and metabolic disorders.[48] Through modulation of TLR4, NF-κB, TNF-α, IL-1, and iNOS targets, it regulates myocardial inflammatory responses and slows disease progression.[49] Asthma pathogenesis closely correlates with vascular cell adhesion molecule-1 (VCAM-1) and ovalbumin-specific immunoglobulin E (OVA sIgE) overexpression. Stigmasterol significantly downregulates VCAM-1 and OVA sIgE expression to inhibit inflammatory cell proliferation and infiltration during asthma,[50] while reducing neurokinin-1 receptor antagonist (NK1-R) expression to relieve airway hyperresponsiveness.[51] Research demonstrates stigmasterol–dexamethasone combination therapy effectively suppresses neutrophil proliferation, oxidative stress, and histone deacetylase 2 levels while increasing IL-17 to beneficially modulate inflammatory characteristics and molecular events in steroid-resistant asthma.[52]

PPI network analysis reveals that Fuzheng Gankang Capsule can act on multiple core targets including IL-1β, IL-6, TNF, TGFB1, PTGS2, and BCL2 to treat CARAS with lung–spleen qi deficiency and wind–cold invading the lung syndrome. IL-1β is produced by activated macrophages and monocytes, functioning as a pro-mucin inflammatory mediator that increases the number of mucus-producing goblet cells.[53] During CARAS attacks, goblet cells enhance mucus secretion, obstruct airway and cause airflow limitation and breathing difficulties.[54] When allergens enter the airway, the immune system activates, and prompts goblet cells to release various inflammatory mediators such as leukotrienes and histamine, which recruit inflammatory cells to the airway.[55] While eosinophils release inflammatory factors, their extracellular traps activate pulmonary neuroendocrine cells through the CCDC25/ILK/PKC α/CRTC1 signaling pathway and amplify allergic immune responses via neuropeptides and neurotransmitters.[56] Goblet cells facilitate inflammatory cell adhesion to airway epithelium through adhesion molecule expression, which enhances inflammatory cell activity. This aggregation of inflammatory cells and release of mediators create a vicious cycle that progressively worsens CARAS inflammation. IL-6, primarily produced by immune cells and epithelial cells, activates multiple inflammatory signaling pathways including STAT3/BCL-2, mediates CARAS inflammation and airway remodeling.[57] Studies show IL-6 promotes ferroptosis by regulating the FXR/PKM2/YAP axis, inhibits alveolar type II epithelial cell regeneration, and accelerates lung injury progression in mice.[58] IL-6 also synergizes with TNF and IL-1β to amplify inflammation, causes airway spasms and increased mucus secretion.[59] TNF, IL-6, and IL-1β can activate downstream TLR4/NF-κB/NLRP3 inflammatory pathways and exacerbate respiratory inflammation.[60] Research indicates PTGS2.8473 gene polymorphism is closely associated with asthma, atopy, and lung function in Chinese children.[61] Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as COX-2, shows low expression under normal conditions but significantly increases when stimulated by inflammatory factors like IL-1β and TNF-α. PTGS2 catalyzes arachidonic acid conversion to prostaglandin H2 (PGH2),[62] activating MAPK, HIF-1, NF-κB, and cAMP inflammatory pathways, further inducing respiratory mucosal edema, increased mucus secretion, and bronchial smooth muscle contraction, thereby aggravating CARAS symptoms.[63] Research indicates that activation of the STAT3/MAPK signaling pathway promotes generation of downstream inflammatory factors including IL-6, IL-1β, and TNF-α.[64]

KEGG pathway enrichment analysis identifies the PI3K/Akt, NF-κB, JAK-STAT, and FoxO signaling pathways as the main pathways through which this formula exerts its effects. PI3K/Akt pathway activation participates in biological processes including cell proliferation/survival, metabolism, angiogenesis, and neuroprotection. Its activation involves growth factor receptor tyrosine kinases, G-protein-coupled receptors, integrins, oxidative stress, DNA damage, and cell cycle factors.[65] NF-κB and FoxO are key downstream molecules of PI3K/Akt signaling.[66] NF-κB, a transcription factor, regulates genes controlling cell proliferation/apoptosis and those involved in inflammation/immune responses. Akt phosphorylates IκB kinase (IKK) to activate NF-κB, promoting expression of cell survival-related genes.[67] Akt also phosphorylates FoxO proteins to inhibit their transcriptional activity. FoxO transcription factors regulate expression of downstream targets like Bcl-2, Bax, and Caspase-3, influencing apoptosis and proliferation.[68] The JAK kinase family comprises JAK1, JAK2, JAK3, and TYK2. Studies show TYK2 and JAK1 phosphorylate STAT1 and STAT2 to activate the IFN-α/β pathway and initiate antiviral immune responses.[69] TYK2 activates IL-12/IL-23 signaling pathways, participating in Th1/Th17 cell differentiation and playing crucial roles in Th1/Th17-mediated immune regulation.[70] Quercetin and luteolin target IL17A, PIK3CB, PIK3CD, Akt1, and TNF to inhibit IL-17 signaling pathway, thereby differentially affecting downstream JAK-STAT, PI3K, Akt, and NF-κB pathways, thus effectively reducing lung inflammation and alleviating cough-variant asthma.[71] Studies show that β-sitosterol inhibits NF-κB signaling pathway to reduce inflammatory mediators while regulating claudin-4/5 expression to enhance lung epithelial barrier function.[72] In obese type 2 diabetic rats, it suppresses inflammation and insulin resistance by downregulating IKK β/NF-κB/JNK signaling pathway.[73] Wogonin inhibits PI3K/Akt pathway activation, reduces VEGF expression, suppresses NF-κB nuclear translocation, decreases NF-κB binding to exogenous DNA oligonucleotides, and inhibits H₂O₂-induced vascular migration and formation.[74]

 

MissingLinkText

Conclusions

Results of this study demonstrate that the main active components of Fuzheng Gankang Pill achieve therapeutic effects on CARAS with lung–spleen qi deficiency and wind–cold invading lung syndrome by acting on core targets such as TNF and PTGS2 through the FoxO, PI3K/Akt, JAK/STAT, and NF-κB signaling pathways. These findings provide valuable references for further research on the molecular mechanisms of Fuzheng Gankang Pill in treating this syndrome pattern.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Xin Wang: Conceptualization, data curation, supervision, and writing-original draft. Ye Pan: Conceptualization, formal analysis, methodology, and software. Suhua Wang: Conceptualization, investigation, supervision, and writing -original draft. Zhiyong Pang: Conceptualization, and project administration. Zhixin Zhao: Data curation and investigation. Juntao Yan: Investigation, and writing -original draft. Kaiwen Dong: Data curation, and investigation. Kun Li: Formal analysis, and investigation. Mingli Zhang: Conceptualization, supervision, and writing -original draft. Junxia Zhang: Project administration.

• References

• 1 Paiva Ferreira LKD, Paiva Ferreira LAM, Monteiro TM, Bezerra GC, Bernardo LR, Piuvezam MR. Combined allergic rhinitis and asthma syndrome (CARAS). Int Immunopharmacol 2019; 74: 105718
• 2 Bao XM. Association between allergic rhinitis and asthma. Chin Health Care Nutr 2016; 26 (26) 30
• 3 Wang XL. Analysis of the association between allergic rhinitis and bronchial asthma. Linchuang Heli Yongyao Zazhi 2019; 12 (28) 123-124
• 4 Khan DA. Allergic rhinitis and asthma: epidemiology and common pathophysiology. Allergy Asthma Proc 2014; 35 (05) 357-361
• 5 Cox LS, Murphey A, Hankin C. The cost-effectiveness of allergen immunotherapy compared with pharmacotherapy for treatment of allergic rhinitis and asthma. Immunol Allergy Clin North Am 2020; 40 (01) 69-85
• 6 Weaver-Agostoni J, Kosak Z, Bartlett S. Allergic rhinitis: rapid evidence review. Am Fam Physician 2023; 107 (05) 466-473
• 7 Zhao J, Zhang M, Li Z. Association between immune-related disease and allergic rhinitis: a two-sample mendelian randomization study. Am J Rhinol Allergy 2024; 38 (01) 31-37
• 8 Kim MH, Sohn KH, Park HJ. et al. Multicenter prospective observational study to evaluate the therapeutic effect and safety of a combination of montelukast and levocetirizine for allergic rhinitis when administered to patients with allergic rhinitis and asthma. Int Arch Allergy Immunol 2022; 183 (12) 1251-1258
• 9 Huang K, Zhang P, Zhang Z. et al. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms. Pharmacol Ther 2021; 225: 107843
• 10 Li PP, Gao SY, Zhang Y. et al. Core prescriptions of Wu Liqun in the treatment of combined allergic rhinitis and asthma syndrome in children and its molecular mechanism. J Pediatr Pharm 2024; 30 (11) 10-17
• 11 Li XH, Jia LL, Liu XX. Preliminary discussion of diagnosis and treatment mode of future medicine from treating based on syndrome differentiation and precision medicine. Chin J Tradit Chin Med Pharm 2018; 33 (11) 4789-4792
• 12 Cui HS, Lv MS, Wang J. et al. Evaluation of studies of prevention and treatment of combined allergic rhinitis and asthma syndrome with TCM. J Beijing Univ Tradit Chin Med 2021; 44 (03) 203-208
• 13 Fan J, Tang XC. Research progress of traditional Chinese medicine treatment for combined allergic rhinitis and asthma syndrome in adults. Chin J Exp Tradit Med Formul 2016; 22 (12) 229-234
• 14 He MX, Sun ZT. Research overview on traditional Chinese medicine treatment for adult allergic rhinitis-asthma syndrome. J Emerg Tradit Chin Med 2021; 30 (03) 551-553
• 15 Lu YZ. Libi Zhixiao Formula in the treatment of combined allergic rhinitis and asthma syndrome (invasion of lung by cold) clinical study. Changchun: Changchun University of Chinese Medicine; 2016
• 16 Wang JQ. Observation of the clinical efficacy of “fortifying earth to generate metal” acupuncture method in the treatment of patients with allergic rhinitis-asthma syndrome and pulmonary spleen qi deficiency syndrome. Chengdu: Chengdu University of Traditional Chinese Medicine; 2024
• 17 Li S, Yang JB, Liao C. et al. Effect of exterior-releasing formula on the impaired nasal mucosal immune barrier function in rats induced by cold stimulation. Zhongchengyao 2022; 44 (01) 227-230
• 18 Jamieson RR, Stasiak SE, Polio SR. et al. Stiffening of the extracellular matrix is a sufficient condition for airway hyperreactivity. J Appl Physiol 2021; 130 (06) 1635-1645
• 19 Xiong J, Chen YQ, Chen RX. [Professor CHEN Ri-xin's academic thought and clinical application of “no allergy without any deficiency”]. Zhongguo Zhenjiu 2020; 40 (02) 199-202
• 20 Maolan A, Li Y, Ren XL. et al. Study on 153 cases with TCM syndrome elements and distribution syndrome types of pulmonary nodules in the elderly. Liaoning J Tradit Chin Med 2025; 52 (02) 5-9
• 21 Sang HY, Li M, Li FZ. Four medical case records of Li Fazhi's pattern differentiation and treatment for allergic rhinitis-asthma syndrome. New Chin Med 2024; 56 (24) 225-228
• 22 Piao CH, Fan Y, Nguyen TV, Song CH, Kim HT, Chai OH. PM2.5 exposure regulates Th1/Th2/Th17 cytokine production through NF-κB signaling in combined allergic rhinitis and asthma syndrome. Int Immunopharmacol 2023; 119: 110254
• 23 Pan M, Zhang L, Chang S. et al. Poly-l-arginine promotes ferroptosis in asthmatic airway epithelial cells by modulating PBX1/GABARAPL1 axis. Int J Biol Macromol 2025; 286: 138478
• 24 Bradding P, Porsbjerg C, Côté A, Dahlén SE, Hallstrand TS, Brightling CE. Airway hyperresponsiveness in asthma: the role of the epithelium. J Allergy Clin Immunol 2024; 153 (05) 1181-1193
• 25 Klimek L, Werminghaus P, Casper I, Cuevas M. The pharmacotherapeutic management of allergic rhinitis in people with asthma. Expert Opin Pharmacother 2024; 25 (01) 101-111
• 26 Feng Y, Qiao H, Liu H, Wang J, Tang H. Exploration of the mechanism of aloin ameliorates of combined allergic rhinitis and asthma syndrome based on network pharmacology and experimental validation. Front Pharmacol 2023; 14: 1218030
• 27 Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol 2022; 19 (12) 775-790
• 28 Yousefzadeh MJ, Flores RR, Zhu Y. et al. An aged immune system drives senescence and ageing of solid organs. Nature 2021; 594 (7861): 100-105
• 29 Adilis Maria Paiva Ferreira L, Karla Diega Paiva Ferreira L, Fragoso Pereira Cavalcanti R. et al. Morita-Baylis-Hillman adduct 2-(3-hydroxy-1-methyl-2-oxoindolin-3-il) acrylonitrile (CISACN) ameliorates the pulmonary allergic inflammation in CARAS model by increasing IFN-γ/IL-4 ratio towards the Th1 immune response. Int Immunopharmacol 2024; 130: 111737
• 30 Chakraborty S, Singh A, Wang L. et al. Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis. J Exp Med 2023; 220 (11) e20221388
• 31 Wang X, Sima Y, Zhao Y. et al. Endotypes of chronic rhinosinusitis based on inflammatory and remodeling factors. J Allergy Clin Immunol 2023; 151 (02) 458-468
• 32 Xu L, Huang X, Chen Z, Yang M, Deng J. Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling. Clin Immunol 2024; 263: 110228
• 33 Bakakos A, Krompa A. Asthma in the era of SARS CoV-2 virus. J Asthma 2022; 59 (08) 1501-1508
• 34 Zhao J, Liu GW, Tao C. Hotspots and future trends of autophagy in Traditional Chinese Medicine: a bibliometric analysis. Heliyon 2023; 9 (10) e20142
• 35 Xu M, Zhang D, Yan J. Targeting ferroptosis using Chinese herbal compounds to treat respiratory diseases. Phytomedicine 2024; 130: 155738
• 36 Ge Z, Xu M, Ge Y. et al. Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation. Cell Rep 2023; 42 (11) 113417
• 37 McCubrey JA, Steelman LS, Chappell WH. et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007; 1773 (08) 1263-1284
• 38 Lee S, Yu Y, Trimpert J. et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature 2021; 599 (7884): 283-289
• 39 Qian W, Liu M, Fu Y. et al. Antimicrobial mechanism of luteolin against Staphylococcus aureus and Listeria monocytogenes and its antibiofilm properties. Microb Pathog 2020; 142: 104056
• 40 Gendrisch F, Esser PR, Schempp CM, Wölfle U. Luteolin as a modulator of skin aging and inflammation. Biofactors 2021; 47 (02) 170-180
• 41 Wang T, Yin Y, Jiang X. et al. Exploring the mechanism of luteolin by regulating microglia polarization based on network pharmacology and in vitro experiments. Sci Rep 2023; 13 (01) 13767
• 42 Zhou BX, Li J, Liang XL. et al. β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling. Acta Pharmacol Sin 2020; 41 (09) 1178-1196
• 43 Jia JF, Zeng MN, Zhang BB. et al. Regulation of Th17/Treg immune imbalance by β-sitosterol in an OVA-inducedallergic asthma rat model. Chin J Immunol 2023; 39 (12) 2477-2482
• 44 Zou Q, Fu DD, Fan TY. et al. Effects and mechanisms of wogonin on airway inflammation in rats with chronic obstructive pulmonary disease. Chin Pharm 2023; 34 (09) 1060-1065
• 45 Ge J, Yang H, Zeng Y, Liu Y. Protective effects of wogonin on lipopolysaccharide-induced inflammation and apoptosis of lung epithelial cells and its possible mechanisms. Biomed Eng Online 2021; 20 (01) 125
• 46 Yeh YC, Yang CP, Lee SS. et al. Acute lung injury induced by lipopolysaccharide is inhibited by wogonin in mice via reduction of Akt phosphorylation and RhoA activation. J Pharm Pharmacol 2016; 68 (02) 257-263
• 47 Wang SC, Sun Y, Wang XX. et al. Effect of wogonin on expression of lung epithelial-mesenchymal formation factorin lung tissue of mycoplasma pneumoniae pneumonia mice. Chin Tradit Herbal Drugs 2023; 54 (01) 172-180
• 48 Zhang X, Yang Z, Su S. et al. Kaempferol ameliorates pulmonary vascular remodeling in chronic hypoxia-induced pulmonary hypertension rats via regulating Akt-GSK3β-cyclin axis. Toxicol Appl Pharmacol 2023; 466: 116478
• 49 Zhao XS. Effect of Kaempferol on Apoptosis of Rat Cardiomyocyte H9c2. Zhengzhou: Zhengzhou University; 2019
• 50 Antwi AO, Obiri DD, Osafo N. Stigmasterol modulates allergic airway inflammation in guinea pig model of ovalbumin-induced asthma. Mediators Inflamm 2017; 2017: 2953930
• 51 Zhang J, Zhang C, Miao L, Meng Z, Gu N, Song G. Stigmasterol alleviates allergic airway inflammation and airway hyperresponsiveness in asthma mice through inhibiting substance-P receptor. Pharm Biol 2023; 61 (01) 449-458
• 52 Hohoayi A, Antwi AO, Amoah V, Osafo N, Sampene PPO, Ainooson G. Coadministration of stigmasterol and dexamethasone (STIG+DEX) modulates steroid-resistant asthma. Mediators Inflamm 2022; 2022: 2222270
• 53 Sponchiado M, Bonilla AL, Mata L. et al. Club cell CREB regulates the goblet cell transcriptional network and pro-mucin effects of IL-1B. Front Physiol 2023; 14: 1323865
• 54 Sudhadevi T, Ackerman SJ, Jafri A. et al. Sphingosine kinase 1-specific inhibitor PF543 reduces goblet cell metaplasia of bronchial epithelium in an acute asthma model. Am J Physiol Lung Cell Mol Physiol 2024; 326 (03) L377-L392
• 55 Cavalcanti RFP, Gadelha FAAF, de Jesus TG. et al. Warifteine and methylwarifteine inhibited the type 2 immune response on combined allergic rhinitis and asthma syndrome (CARAS) experimental model through NF-кB pathway. Int Immunopharmacol 2020; 85: 106616
• 56 Lu Y, Huang Y, Li J. et al. Eosinophil extracellular traps drive asthma progression through neuro-immune signals. Nat Cell Biol 2021; 23 (10) 1060-1072
• 57 Qin B, Zhou Z, He J, Yan C, Ding S. IL-6 inhibits starvation-induced autophagy via the STAT3/bcl-2 signaling pathway. Sci Rep 2015; 5: 15701
• 58 Yang D, Liang H, Zhu X. et al. Farnesoid X receptor protects murine lung against IL-6-promoted ferroptosis induced by polyriboinosinic-polyribocytidylic acid. Am J Respir Cell Mol Biol 2024; 70 (05) 364-378
• 59 Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS. et al. COVID-19 infection: an overview on cytokine storm and related interventions. Virol J 2022; 19 (01) 92
• 60 Zeng Y, Cao W, Huang Y. et al. Huangqi Baihe granules alleviate hypobaric hypoxia-induced acute lung injury in rats by suppressing oxidative stress and the TLR4/NF-κB/NLRP3 inflammatory pathway. J Ethnopharmacol 2024; 324: 117765
• 61 Chan IH, Tang NL, Leung TF. et al. Association of prostaglandin-endoperoxide synthase 2 gene polymorphisms with asthma and atopy in Chinese children. Allergy 2007; 62 (07) 802-809
• 62 Alvarez AM, DeOcesano-Pereira C, Teixeira C, Moreira V. IL-1β and TNF-α modulation of proliferated and committed myoblasts: IL-6 and COX-2-derived prostaglandins as key actors in the mechanisms involved. Cells 2020; 9 (09) 2005
• 63 Liu C, Zhang HY, Nie J. et al. Molecular mechanism on Biyuan Tongqiao Granules in treatment of allergic rhinitis based on network pharmacology. World Chin Med 2022; 17 (12) 1658-1665
• 64 Jiang Y, Nguyen TV, Jin J, Yu ZN, Song CH, Chai OH. Bergapten ameliorates combined allergic rhinitis and asthma syndrome after PM2.5 exposure by balancing Treg/Th17 expression and suppressing STAT3 and MAPK activation in a mouse model. Biomed Pharmacother 2023; 164: 114959
• 65 Wang J, Hu K, Cai X. et al. Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis. Acta Pharm Sin B 2022; 12 (01) 18-32
• 66 Sun EJ, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Biomedicines 2021; 9 (11) 1639
• 67 Guo Q, Jin Y, Chen X. et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9 (01) 53
• 68 Andrade J, Shi C, Costa ASH. et al. Control of endothelial quiescence by FOXO-regulated metabolites. Nat Cell Biol 2021; 23 (04) 413-423
• 69 Pellegrini S, Dusanter-Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem 1997; 248 (03) 615-633
• 70 Wu DD, Cao X, An YP. Syndrome differentiation and treatment of psoriasis by regulating classical JAK/STAT signaling pathway with traditional Chinese medicine: a review. Chin J Exp Tradit Med Formul 2023; 29 (01) 258-269
• 71 Wang Y, Sui Y, Yao J. et al. Herb-CMap: a multimodal fusion framework for deciphering the mechanisms of action in traditional Chinese medicine using Suhuang antitussive capsule as a case study. Brief Bioinform 2024; 25 (05) bbae362
• 72 Chen X, Chen J, Ren Y. et al. β-sitosterol enhances lung epithelial cell permeability by suppressing the NF-κB signaling pathway. Discov Med 2023; 35 (179) 946-955
• 73 Jayaraman S, Devarajan N, Rajagopal P. et al. β-sitosterol circumvents obesity induced inflammation and insulin resistance by down-regulating IKK β/NF-κB and JNK signaling pathway in adipocytes of type 2 diabetic rats. Molecules 2021; 26 (07) 2101
• 74 Zhou M, Song X, Huang Y. et al. Wogonin inhibits H2O2-induced angiogenesis via suppressing PI3K/Akt/NF-κB signaling pathway. Vascul Pharmacol 2014; 60 (03) 110-119

Publication History

Received: 28 January 2025

Accepted: 27 March 2025

Article published online:
27 June 2025