Abstract: This study aimed to investigate the molecular mechanism by which astrocyte elevated gene 1 (AEG-1) upregulates the transcriptional expression of eukaryotic translation initiation factor 4E (eIF4E) and its role in the sensitivity of gastric cancer cells to cisplatin (CDDP). Transcriptomic analysis and TCGA database correlation analysis were used to screen potential transcriptional regulatory mechanisms of AEG-1. In gastric cancer BGC823 and MGC803 cell lines, plasmid overexpression, siRNA interference, and pharmacological inhibition were applied. The expression changes of eIF4E were detected by qRT-PCR and Western blot. Co-immunoprecipitation (Co-IP) was performed to verify the interaction between AEG-1 and p300 and the binding changes following CXCL12 stimulation. The sensitivity to CDDP and apoptosis levels were measured by SRB assay and flow cytometry, respectively. The results showed that transcriptomic and database analyses suggested that AEG-1 might regulate eIF4E expression through acetylation‑related mechanisms, and EP300 was positively correlated with MTDH and EIF4E in gastric cancer tissues. Functional experiments confirmed that AEG-1-mediated upregulation of eIF4E was dependent on p300. The phosphorylation status of AEG‑1 at serine 426 (S426) affected its regulatory activity on eIF4E and binding to p300, and CXCL12 stimulation enhanced their interaction. Furthermore, AEG‑1 was involved in regulating CDDP sensitivity in gastric cancer cells, and its phosphorylation status was closely associated with the chemoresistant phenotype. In conclusion, AEG-1 enhances the transcriptional expression of eIF4E in a p300-dependent manner, and phosphorylation at the S426 site serves as a key regulatory switch. The AEG-1/p300/eIF4E axis modulates CDDP chemosensitivity in gastric cancer, providing a novel theoretical basis and potential intervention targets for precision therapy of gastric cancer.