Objective To investigate the anti-effects of N-acetyl-seranyl-aspartate-lysyl-proline (Ac-SDKP) on experimental silicosis by regulating YEATS domain-containing protein 4 (YEATS4). Methods RAW264. 7 cells were divided into a siRNA-negative control (NC) group (siC), siRNA-YEATS4 group (siY), silicon dioxide (SiO₂ ) + siRNA- NC group (S+siC), and SiO₂ + siRNA-YEATS4 group ( S +siY). In addition, there was a control group ( C), SiO₂ - induced group (S), SiO₂+ Ac-SDKP treatment group ( S+Ac), and AC-SDKP treatment group (Ac). Wistar rats were randomly divided into a control 24-week group (C24), silicosis 24-week group ( S24), and Ac-SDKP treatment 24-week group (Ac24). Expression of collagen type I (COL I), monocyte chemoattractant protein-1 (MCP-1), arginase 1, and YEATS4 were measured by western blotting in lung tissue and RAW264. 7 cells. Immunohistochemical staining was used to detect YEATS4 expression and localization in lung tissue and RAW264. 7 cells. Results Western blot showed down- regulated protein expression levels of COL I, MCP-1, and arginase 1 in the siY and S+siY groups compared with the siC and S+siC groups (P< 0. 05). Compared with the C group, the levels of COL I, MCP-1, arginase, and YEATS4 were increased in the S group. In addition, the levels of COL I, MCP-1, arginase 1, and YEATS4 were reduced in the S+Ac group compared with the Sgroup in RAW264. 7 cells ( P< 0. 05). Immunohistochemistry and Western blot showed that expression of COL I, MCP-1, arginase-1, and YEATS4 was up-regulated in the S24 group compared with the C24 group. Expression of COL I, MCP-1, arginase-1, and YEATS4 in the Ac24 group was decreased compared with S24 silicosis rats (P< 0. 05). Conclusions Ac-SDKP may play a suppressing role in silicosis by inhibiting YEATS4.