Objective: To investigate the effects of S-phase kinase related protein 2(SKP2) on airway hyperresponsiveness and inflammation induced by ovalbumin in mice with asthma. Methods: Forty male 6-week-old C57BL/6J mice were adaptively fed for one week and randomly divided into normal control group, model group, negative control(LV-shNC) group, and drug treated(LV-shSKP2) group, with 10 mice in each group. Except for the normal control group mice, mice in the other three groups were intraperitoneally injected with ovalbumin(OVA) to establish mouse asthma model. Among them, mice in LV-shNC and LV-shSKP2 groups were injected with LV-shNC and LV-shSKP2 via the tail vein, respectively, at a dose of 2×10⁸ TU·time^-1, once every 2 weeks. Mice in normal control group and model group were injected with equal volume of physiological saline via the tail vein. After 8 weeks, bronchial provocation test(BPT) was used to measure airway resistance and lung compliance in each group; The lung function of each group was assessed using a lung function testing system; Enzyme linked immunosorbent assay(ELISA) was used to detect the levels of immunoglobulin A(IgA), immunoglobulin M(IgM), and immunoglobulin G(IgG) in bronchoalveolar lavage fluid; ELISA kit was used to detect the levels of inflammatory factors tumor necrosis factor alpha(TNF- α), interleukin- 1β(IL-1β), and interleukin-6(IL-6) in serum; Real time reverse transcription quantitative polymerase chain reaction(RT-qPCR), Western blot, and immunofluorescence were used to detect the expression level of SKP2 and the related pathway proteins CDK, Cyclins, P53 protein in lung tissue; Hematoxylin and eosin(HE) staining was used to observe the pathological changes in lung tissue. Results: In vivo experiments in mice showed that compared with the LV-shNC group, in the LV-shSKP2 group the mRNA and protein levels of SKP2 and the related pathway proteins CDK, Cyclins, P53 molecules in the lung tissue of mice were significantly reduced(P<0.05); The airway resistance value of mice was significantly reduced(P<0.05), and the lung compliance was significantly increased(P<0.05); The forced expiratory volume in 100 ms/forced vital capacity(FEV100/FVC), maximum mid expiratory flow(MMEF), and peak expiratory flow(PEF) of mice were significantly increased(P<0.05); The levels of immune markers IgA, IgM, and IgG in mouse bronchoalveolar lavage fluid were significantly increased(P<0.05); The levels of TNF- α, IL-1 β, and IL-6 in serum were significantly reduced on average(P<0.05); The alveolar wall in mouse lung tissue partially recovered to normal thickness, the secretion in the alveolar cavity significantly decreased, the alveolar epithelial cells gradually recovered, the glandular structure gradually normalized, the vascular structure recovered, and the overall tissue structure was relatively intact. Conclusion: Inhibiting SKP2 protein can significantly reduce the level of the related pathway proteins CDK, Cyclins, P53 molecules, reduce airway resistance, improve lung compliance, improve lung function in mice, enhance immune status, and reduce serum levels of inflammatory factors.