〔Abstract〕 To investigate the regulatory effect of overexpressed protein tyrosine phosphatase non - receptor type 2（Ptpn2）on the inflammatory response of mouse alveolar macrophages（MH-S）induced by SiO ₂ . Methods Cells with overexpressed Ptpn2 were constructed and induced by SiO ₂ . The experimental groups were divided into four groups：the negative control group with an empty vector（NC）， the overexpressed Ptpn2 group （P），the negative control group with an empty vector + SiO ₂ induction（NS），and the overexpressed Ptpn2 + SiO ₂ induction group（ PS）. Isobaric tags for relative and absolute quantification（iTRAQ） combined with liquid chromatography-tandem mass spectrometry（ LC-MS/MS）were used to screen differential proteins，followed by Gene Ontology（GO）and Kyoto Encyclopedia of Genes and Genomes（KEGG）database analyses. Immunofluores- cence staining was used to detect the expressions of Tumor necrosis factor（TNF）α , Gasdermin D（GSDMD），and Transforming growth factor（TGF）-β1. Western blot was used to detect the protein expression levels of PTPN2， Toll-like receptor 4（TLR4），tumor necrosis factor-α（TNF-α), nucleotide-binding oligomerization domain-like re- ceptor protein 3（NLRP3）， and proteins related to the TGF-β1 signaling pathway in the cells of each group. Re ⁃ sults iTRAQ results identified 144 differential proteins among the four groups. GO analysis showed that in bio- logical processes（BP），these differential proteins were mainly enriched in IκB kinase/nuclear factor-κB（NF-κB） signaling，cell activation and signal transduction involved in immune responses，and regulation of receptor signal- ing pathways by signal transducer and activator of transcription（STAT），etc. KEGG analysis revealed that the dif- ferential proteins were mainly enriched in Toll-like receptor signaling pathway，NF-κB signaling pathway，NOD- like receptor signaling pathway，TGF-β signaling pathway，and TNF signaling pathway. The results of immunofluo- rescence staining showed that compared with the NC group，the expressions of TNF α , GSDMD，and TGF-β1 in the cells of the NS group increased（P < 0. 05）；Compared to the NS group，the expression of the aforementioned proteins in the PS group decreased in cellular proteins（P < 0. 05）. The results of Western blot showed that com- pared with the NC group，the protein expression levels of PTPN2，p-NF-κB、MyD88、TLR4、NLRP3、GSDMD、Cas- pase-1、IL-1β、TGF-βR1、TGF-βR2、p-Smad2/3 in the NS group were significantly upregulated（P < 0. 05）；Com- pared with the NS group，the expression levels of the aforementioned proteins in the PS group were significantly downregulated（P < 0. 05）. Conclusion Overexpression of Ptpn2 can inhibit the protein expressions of TLR4- TNF-α signaling，NLRP3 signaling，and TGF-β1 signaling closely related to inflammatory response in SiO ₂ -medi- ated MH-S macrophages.