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To explore the mechanism of action of Shengjiang Pingchuan Zhike Pills in the treatment of bronchial asthma, this study used proteomics technology to analyze the key proteins and molecular mechanisms of the ovalbumin(OVA)-induced bronchial asthma in rats and experimentally verified the core differential proteins. Sixty specific-pathogen free(SPF) rats were selected and divided into a blank group and a model group. The model was established by intraperitoneal injection and nebulization of OVA and aluminum hydroxide mixed solution. After successful modeling, the rats were divided into a blank group, a model group, a positive control group, and low-dose, medium-dose, and high-dose groups of Shengjiang Pingchuan Zhike Pills, with 10 rats in each group. The general conditions of the rats in each group were observed. The pathological changes of lung tissue were observed by hematoxylin-eosin(HE) staining, and mucus secretion, as well as basement membrane destruction and thickening were examined by periodic acid-Schiff(PAS) staining. Differentially expressed proteins and molecular mechanisms were analyzed by proteomics. The content of cytokines in bronchoalveolar lavage fluid(BALF) was verified by enzyme-linked immunosorbent assay(ELISA). The location of goblet cells and nuclear translocation of nuclear factor-κB(NF-κB) were measured by immunofluorescence, and the pathways and expression level of key proteins were verified by Western blot. Compared with those of the model group, after the intervention of Shengjiang Pingchuan Zhike Pills, the number of wheezing, stridor, and coughing times decreased; the hair luster and mental state improved; the activity increased; the breathing frequency tended to be stable; the response to external stimuli and flexibility increased, and the body weight showed an increasing trend. Pathological staining showed that after the intervention, the inflammatory infiltration of asthma rats was reduced; the thickening of airway smooth muscle was alleviated; the mucus secretion was decreased; the destruction of the basement membrane was ameliorated, and the inflammatory score and PAS score were decreased. ELISA results indicated that the expression level of interleukin-4(IL-4), interleukin-5(IL-5), interleukin-13(IL-13), and interleukin-17(IL-17) in the high-dose group decreased, and the expression level of interferon(INF)-γ increased. Immunofluorescence results showed that the number of goblet cells and mucus secretion in the high-dose group decreased; the fluorescence of phospho-NF-κB(p-NF-κB) in the nucleus weakened, and some were distributed from the nucleus to the cytoplasm. Western blot results showed that the high-dose group exhibited the down-regulated expression of cathepsin S(CTSS), mucin 5AC(MUC5AC), and p-NF-κB/NF-κB proteins and the up-regulated expression of low-affinity immunoglobulin γFc region receptor Ⅱ-b(FCGR2B) protein. In conclusion, Shengjiang Pingchuan Zhike Pills may alleviate OVA-induced airway inflammation, goblet cell metaplasia, and mucus secretion by inhibiting the NF-κB pathway, which may be related to the down-regulation of CTSS and up-regulation of FCGR2B protein expression, thereby regulating the immune balance of Th1/Th2/Th17 cells.