Objective: Gastric cancer (GC) is a common tumor with a high metastasis rate worldwide. Tripartite motif containing 21 (TRIM21) plays a crucial role in regulating many cellular events involved in tumor progression. However, the mechanism by which TRIM21 mediates gastric cancer proliferation through the PI3K/AKT pathway is unclear. In this study, we discussed the mechanism of TRIM21 regulating gastric cancer proliferation through the PI3K/AKT signaling pathway. Methods: PCR and ELISA were used to explore the differential expression of TRIM21 in the human gastric mucosal cell line GES-1 and the human gastric cancer cell lines NUGC4, MKN1 and MKN45, and the highly expressed cell line NUGC4 was selected for subsequent experiments. TCGA gastric cancer samples were used to analyze TRIM21 RNA and protein expression differences in histology. The cell transfection constructed NC arm, siTRIM21-#1 arm and siTRIM21-#2 arm, to explore the expression and function of TRIM21 in NUGC4 cell lines, including RNA expression by PC humans, protein expression by ELISA, cell proliferation by cloning experiments and PIISA by PI3K/AKT signaling pathway. Results: Compared with the human gastric mucosal cell line GES-1, the expression of TRIM21 in gastric cancer cells NUGC4, MKN1 and MKN45 was significantly increased, and the difference was statistically significant (FDR<0.05), and TRIM21 expression levels were highest in NUGC4 cells. Analysis of TCGA gastric cancer samples showed that the transcription level and protein level of TRIM21 were highly expressed in cancer tissues, and there was a statistically significant difference between cancer and para-cancer (p<0.05). Cells successfully transfected. Compared with the blank control group and siRNA-NC group, the proliferation inhibition rate of NUGC4 cells in the TRIM21-siRNA group was significantly increased (FDR<0.05), and the expression of p-PI3K and p-AKT was significantly reduced (FDR<0.05). Conclusion: TRIM21 is an oncogene in gastric cancer, and silencing TRIM21 expression can inhibit the proliferation of gastric cancer cells, which may be achieved by inhibiting the PI3K/AKT signaling pathway.