〔Abstract〕 To explore the role of the histone deacetylase Sirtuin-1（SIRT1）/p53 signaling pathway in promoting apoptosis of non-small cell lung cancer cells（NSCLC）induced by the co-stimulatory molecule B7 homo- log 3（B7-H3）. Methods The GEPIA 2 platform was used for survival analysis of NSCLC patients based on B7⁃ H3 gene expression levels. The Gene Enrichment Analysis（GSEA）method was used to analyze the enrichment characteristics of B7⁃ H3 molecules in the gene set of cell apoptosis. In the non-small cell lung cancer A549 cell line，B7⁃ H3 was knocked down，and the protein expression levels of SIRT1 and p53 were detected by Western blot. B7⁃H3 was overexpressed in A549 cells and the apoptosis rate was analyzed by flow cytometry after Annexin V/PI double staining. Overexpression of B7⁃H3 and knockdown of SIRT1 were performed in A549 cell line. The ex- pression levels of p53 and apoptosis-related proteins B-cell lymphoma/leukemia-2（Bcl-2）and Bcl-2-associated X protein（Bax）were detected respectively by Western blot. Cell apoptosis rate was analyzed by flow cytometry after Annexin V/PI double staining. Results The overall survival of the B7-H3 high-expression group was significantly lower than that of the low-expression group（P<0. 01）. B7-H3 was significantly enriched in the cell apoptosis sig- naling pathway and the p53 signaling pathway（P<0. 05）. Compared with the control group，the expression of SIRT1 was significantly downregulated，and p53 was significantly upregulated in the B7 ⁃ H3 knockdown group （both P<0. 001）. Overexpression of B7-H3 significantly up-regulated SIRT1 protein expression（P<0. 05），down- regulated p53 expression（P<0. 01），and markedly increased the Bcl-2/Bax ratio of apoptosis-related proteins（P< 0. 001）. The results of Annexin V/PI double staining showed that the apoptosis rate of A549 cells with overex- pressed B7⁃ H3 decreased（the apoptosis rate of the control group was 26. 72%±4. 13%，while that of the B7⁃ H3 overexpression group was 13. 87%±0. 82%；P<0. 01）. In B7-H3-overexpressing cell lines，SIRT1 knockdown sig- nificantly reversed apoptosis（P<0. 05），up-regulated p53 protein expression（P<0. 001），and markedly reduced the Bcl-2/Bax ratio（P<0. 001）. Conclusion B7-H3 molecule inhibits the apoptosis of non-small cell lung cancer cells via the SIRT1/p53 signaling pathway.