Abstract: Objective To explore the effect of Sangxing Zhike Formula in rats with cough variant asthma (CVA) and its possible mechanism based on the cyclic adenosine monophosphate (cAMP)/cystic fibrosis transmembrane conductance regulator (CFTR) pathway. Methods SD rats were randomly divided into control group, model group, dexamethasone group (0.5 mg/kg) and low-, medium-, high-dose Sangxing Zhike Formula groups (9.6, 19.2 and 38.4 g/kg) using a random number table method, with 9 rats in each group. Except for the control group, CVA rat models were established in the other groups. Rats in each group were administered the drug by gavage once a day for 14 consecutive days. The general conditions of rats in each group were observed. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in rat serum. Hematoxylin-eosin (HE) staining and periodic acid-Schiff (PAS) staining were used to observe the pathological changes in rat lung and bronchial tissues, and the acid-base balance of airway surface liquid (ASL) was measured. Western blot and real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression levels of protein kinase A (PKA), CFTR protein and their mRNA in lung tissues of rats. Results Compared with the control group, rats in the model group showed listlessness, dull fur, slow weight gain, a significantly expanded area of alveolar septal consolidation, and a large number of inflammatory cell infiltrations around the bronchi. Compared with the model group, rats in each intervention group had better general conditions and reduced inflammatory infiltrations in lung tissues and bronchial lumens. Compared with the control group, the serum levels of IL-1β and IL-18 in the model group were increased, and the pH values of ASL in the model group, low-dose Sangxing Zhike Formula group, medium-dose Sangxing Zhike Formula group, and high-dose Sangxing Zhike Formula group were all decreased, with statistically significant differences (P < 0.05). Compared with the model group, the serum levels of IL-1β and IL-18 in each intervention group were decreased, and the pH values of ASL in the dexamethasone group, medium-dose Sangxing Zhike Formula group, and high-dose Sangxing Zhike Formula group were increased, with statistically significant differences (P < 0.05). Compared with the control group, the expressions of PKA protein and PKA mRNA in the model group, low-dose Sangxing Zhike Formula group, and medium-dose Sangxing Zhike Formula group were all decreased, and the expressions of CFTR protein and CFTR mRNA in the model group and each intervention group were all decreased, with statistically significant differences (P < 0.05). Compared with the model group, the expressions of PKA protein and PKA mRNA in the dexamethasone group and high-dose Sangxing Zhike Formula group were increased, and the expressions of CFTR protein and CFTR mRNA in the high-dose Sangxing Zhike Formula group were increased, with statistically significant differences (P < 0.05). Conclusion Sangxing Zhike Formula can improve the general conditions of CVA rats, regulate the acid-base balance of ASL, reduce airway inflammatory cell infiltration andairway remodeling, and decrease the levels of inflammatory factors IL-1β and IL-18. Its mechanism may be related to the cAMP/CFTR pathway.