Objective To explore the effects of N-acetyl-seryl-aspartyl-lysyl-proline ( Ac-SDKP) on alveolar type II epithelial cellular senescence during experimental silicosis. Methods The HOPE-MED8050 dynamic silica dust exposure control system was applied to establish a rat model of silicosis, and the experimental silicosis rats were divided into the control, dust-treated and Ac-SDKP post-treatment groups. MLE-12 cells were cultured in vitro, and the experimental cells were divided into the control, SiO2 -induction, Ac-SDKP and SiO2 + Ac-SDKP groups. Sirius red staining was used to observe collagen deposition in the lung tissue; immunofluorescence staining was used to detect the location of p21, and immunoblotting was used to detect type I collagen (Col I) expression, p-capillary dilatation ataxia mutant kinase (ATM) , p-capillary dilation ataxia (ATR) , p-p53, p21 and p16. Results The lung tissue of rats in the silicosis group could be observed with silicon nodules and collagen deposition. Immunofluorescence staining result showed that p21 was mainly localized in alveolar type II epithelial cells. Immunoblotting result showed upregulated Col I, p- ATM, p-ATR, p-p53, p21 and p16 protein expression levels in the lung tissue. Compared with those of the dust-treated group, the number and area of the silicon nodules in the lungs of the Ac-SDKP post-treated group were significantly reduced, and the protein expression levels of Col I, p-ATM, p-ATR, p-p53, p21 and p16 in the lung tissue were decreased (P<0. 05) . Compared with those of the control group, the Col I, p-ATM, p-ATR, p-p53, p21 and p16 levels in MLE-12 cells of the SiO2 -induced group were upregulated. Compared with those of the SiO2 -induced group, the Col I, p-ATM, p-ATR, p-p53, p21, p16 expression levels were downregulated in the SiO2 + Ac-SDKP group ( P< 0. 05) . Conclusions Ac-SDKP reduced collagen deposition by inhibiting activation of senescence-related signals in alveolar type II epithelial cells.