Objective To investigate the effect and mechanism of N⁃acetyl⁃seranyl⁃aspartate⁃lysyl⁃proline （Ac ⁃ SDKP） in inhibiting experimental silicosis by regulating secreted phosphoprotein 1 （SPP1）/transforming growth factor⁃β1（TGF⁃β1）signaling. Methods Wistar rats were randomly divided into control 24 week group， silicosis 24 week group and Ac⁃SDKP treatment group. RAW264.7 cells were divided into control group，SiO2 induced group and SiO2 + Ac ⁃ SDKPtreated group. As well as control group，recombinant SPP1 induced group， SPP1+Ac⁃SDKP group and SPP1+LY364947 group. Immunohistochemical staining（IHC）was used to detect SPP1 expression and localization. The expression of COL I，monocyte chemoattractant protein ⁃1（MCP ⁃1），TGF ⁃β1， TGF⁃β receptor type I（TGFβRI），TGFβRII，p⁃Smad2/3，Smad2/3 and SPP1 in lung tissue and RAW264.7 cells were measured by western blot. Results IHC and western blot results showed that compared with the control group， the expressions of COL I，MCP⁃1，TGF⁃β1 and SPP1 in the silicosis group were up⁃regulated，and the expressions of COL I，MCP ⁃1，TGF ⁃β1 and SPP1 in the Ac ⁃SDKP group were decreased compared with the silicosis group （P < 0.05）. Compared with the control group，the protein expression levels of COL I，MCP⁃1，TGF⁃β1 and SPP1 were up⁃regulated in the SiO2 ⁃induced group. In addition，the expression levels of COL I，MCP⁃1，TGF⁃β1 and SPP1 in the Ac⁃SDKP treated group were down⁃regulated compared with SiO2⁃induced group（P < 0.05）. Compared with the control group，TGFβRI，TGFβRII andp⁃Smad2/3 were up⁃regulated in the SPP1 induced group. Compared with the SPP1 induced group，the expression of TGFβRI，TGFβRII andp⁃Smad2/3 were down⁃regulated in the Ac⁃SDKP group and LY364947 group（P < 0.05）. Conclusion Ac⁃SDKP can play a suppressing silicosis role by inhibiting the SPP1/TGF⁃