Exploring the molecular mechanism of Huangqi in treating idiopathic pulmonary fibrosis based on network pharmacology and molecular docking
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by progressively worsening respiratory distress and irreversible decline in lung function. This disease is affected by a combination of factors such as inflammation, lung injury, immune response, and fibrosis during its development, resulting in pathological manifestations such as alveolar damage, fibroblast proliferation, and extensive deposition of extracellular matrix (ECM) in the body. At present, the number of IPF patients in China is increasing year by year, and the prognosis is poor. At present, Western medicine mainly treats idiopathic pulmonary fibrosis with glucocorticoids, cytotoxic drugs, and immunosuppressants. Numerous clinical and experimental studies have shown that traditional Chinese medicine has a significant improvement effect on multiple pathological stages of IPF, which can enhance patients’ quality of life, reduce mortality rates, and have good application prospects. Based on data mining analysis, the frequency of using traditional Chinese medicine tonics in the treatment of such diseases is as high as 55%, with Huangqi being used 148 times, ranking first. This indicates that Huangqi plays an important role in the treatment of idiopathic pulmonary fibrosis.

Astragalus membranaceus is sweet in taste, slightly warm in nature, and can regulate the spleen and lung meridians. It has the effects of tonifying the spleen, promoting yang, nourishing the lungs, and strengthening the surface. It is commonly used to strengthen the body and strengthen the body. The “Shennong Bencao Jing” records that it is “mainly used for treating carbuncle and gangrene… supplementing deficiency” and is one of the main traditional Chinese medicines for clinical prevention and treatment of multiple organ fibrosis. There are many active ingredients in Huangqi, mainly including Huangqi saponins, Huangqi polysaccharides, flavonoids, and triterpenoids. At present, the chemical composition and active ingredients of Astragalus membranaceus have received widespread attention. With the continuous deepening of research on the pharmacological effects of Astragalus membranaceus, Astragalus membranaceus glycoside IV, Astragalus polysaccharides, Astragalus total saponins, and Astragalus injection have achieved therapeutic effects in the treatment of IPF. Therefore, this study takes the chemical components of Astragalus membranaceus as the starting point, and explores the key active ingredients and regulatory targets of Astragalus membranaceus in the treatment of IPF through network pharmacology and molecular docking techniques, providing theoretical basis for the development and clinical use of Astragalus membranaceus.

Idiopathic pulmonary fibrosis (IPF) is the most common pulmonary disease of unknown etiology, characterized by chronic progressive exacerbation that is difficult to reverse. It is a comprehensive result of four factors: inflammatory response, lung injury, immune response, and fibrosis. IPF affects approximately 3 million people worldwide, mostly in middle-aged and elderly individuals, characterized by progressively worsening respiratory distress and irreversible decline in lung function, with poor prognosis. IPF has a low survival rate and a high incidence rate, which is called “tumor like disease”. Once diagnosed, the survival rate of patients will decline year by year. The 3-year duration of illness can still guarantee a 50% survival rate. Once it reaches 5 years, its survival rate will decline to only 20%, which is a major disease seriously endangering public health.

Astragalus membranaceus is a nourishing herb that mainly enters the lungs and spleen meridians. Due to its wide range of effects and clear efficacy, it has become one of the most commonly used traditional Chinese medicines in clinical treatment of pulmonary fibrosis. Its chemical composition is diverse, and pharmacological studies have shown that Astragalus membranaceus can enhance immune function, with anti-inflammatory, antibacterial, antiviral, and anti hypoxia effects. It can reduce collagen content in the lungs and is one of the main traditional Chinese medicines for clinical prevention and treatment of multiple organ fibrosis. Currently, most published literature focuses on the main components of Astragalus membranaceus, such as Astragaloside IV and Total Flavonoids of Astragalus membranaceus. This study found through bioinformatics that the component target network diagram of Astragalus membranaceus for treating IPF showed high connectivity between six compounds, including isorhamnetin and folate, and multiple targets of IPF. Molecular docking results suggest that these components may play a role in the treatment of IPF with Astragalus membranaceus. Zheng et al. confirmed that isorhamnetin can protect against bleomycin induced pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial mesenchymal transition; Kawami et al. found that folic acid may effectively inhibit MTX induced lung injury; Yao et al. found that the expression of folate receptor β in macrophages plays a pathogenic role in IPF, and targeted therapy targeting macrophages expressing folate receptor β may be an effective method for treating IPF.

The analysis of GO and KEGG signaling pathways showed that the target pathways involved in Huangqi’s treatment of IPF are mainly related to inflammatory response and oxidative stress. Combined with the analysis results and literature research, it was found that the IL-17 signaling pathway, EGFR signaling pathway, and HIF-1 signaling pathway have a high correlation with IPF. Xu et al. found that IL-17 can serve as an auxiliary diagnostic indicator for pulmonary fibrosis, predict drug efficacy, and evaluate treatment effectiveness; Pan et al. found that the expression level of IL-17 in COPD patients was significantly increased, and the inflammatory response persisted; Ma et al. found that the PEI of CBPP, as a lead compound, can improve lung function and alleviate pulmonary fibrosis by acting on the EGFR and MLC2 signaling pathways; Wang et al. confirmed through research that paraquat can activate the HIF-1 α signaling pathway to initiate the epithelial mesenchymal transition program, thereby inducing the development of pulmonary fibrosis.

The PPI network analysis results showed that PTGS2, VEGFA, MMP-9, STAT3, and EGFR were key targets. Molecular docking results indicated that the chemical components of Astragalus membranaceus could bind well to them. Currently, previous studies have shown that these targets play an important role in IPF. Wang et al. found that the method of tonifying qi, warming yang, promoting blood circulation, and promoting diuresis can improve kidney injury and reduce fibrosis. The mechanism may be to regulate the PTGS2/NOX1 signaling pathway, thereby reducing ROS levels and decreasing cell iron death; Experiments induced by BLM in rats showed that inhibiting VEGF may reduce fibrosis, while overexpression of VEGF exacerbates the progression of pulmonary fibrosis; Luan et al. found that Astragaloside IV can exert anti pulmonary fibrosis effects by reducing the expression levels of VEGF and VEG-FR2 genes; MMP-9 is a type IV collagenase that can degrade collagen ECM and other components distributed in the lung basement membrane and interstitium, leading to lung injury and initiating the development of lung fibers. Ren et al. found that the formula of promoting lung collaterals and replenishing qi can regulate the imbalance of MMP-9/IMP1, reduce the excessive deposition of FN and Col IV, improve rat lung function, and inhibit the occurrence and development of rat pulmonary fibrosis; Wu et al. found that knocking out the STAT3 gene in mice increases STAT3 activity expression and reduces fibroblast apoptosis, making them more susceptible to BLM induced pulmonary fibrosis. This suggests that STAT3 protein may promote the occurrence of pulmonary fibrosis. The EGF family, represented by epidermal growth factor (EGF), and its receptor EGFR play an important role in the course of pulmonary fibrosis. Li et al. found that the expression level of EGFR in different groups of lung tissue injury in rats exposed to bleomycin had significant differences. The expression level of EGFR in the lung tissue of IPF group patients was significantly higher than that of the control group patients, suggesting that the occurrence of IPF may be related to high expression of EGFR.

The results of HE staining and Masson staining showed that there were a large number of inflammatory cells accumulated in the lungs of IPF rats, and the degree of collagen proliferation was significantly increased. Pathological changes occurred in the lung tissue structure, and collagen tissue replaced the normal alveolar structure, resulting in impaired respiratory function of the lungs. After treatment with folic acid and astragalus, the pathological situation improved, and the therapeutic effect of astragalus was more significant. The ELISA results of experimental rat serum showed that the levels of IL-17 and MMP-9 in the model control group and two drug treatment groups were significantly increased compared with the blank control group, with the model control group having the highest levels. The intervention effects of two drug treatment groups showed that the serum IL-17 and MMP-9 levels in the Huangqi group were significantly lower than those in the folic acid group. From a trend perspective, the levels of IL-17 and MMP-9 in the serum of rats in the drug treatment group were reduced compared to the model control group, indicating that it can exert an anti IPF effect by inhibiting the expression of IL-17 and MMP-9 in the serum of IPF rats.

In summary, this study applied bioinformatics methods to analyze the components and targets of Astragalus membranaceus in treating IPF. Through experiments, it was verified that the active ingredients of Astragalus membranaceus have therapeutic effects on IPF, indicating the rationality of screening. The experimental results preliminarily identified the key targets and active ingredients of Astragalus membranaceus in preventing and treating IPF, and the therapeutic effect of Astragalus membranaceus was better than that of its active ingredient folic acid. This indirectly reflects the characteristic of Astragalus membranaceus in treating IPF through the synergistic effect of multiple components, targets, and pathways. However, due to the complex chemical composition of traditional Chinese medicine, the detailed mechanism of action needs further exploration.