Objective To explore the roles of glutathione peroxidase 4 (GPX4), phosphorylated mammalian target of rapamycin (p-mTOR), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) in the development of gastric cancer and precancerous lesions, analyze their mutual influences, explore the expression levels of GPX4 in gastric cancer, atrophic gastritis, and normal gastric mucosa, and ultimately predict the prognosis of patients. At the same time, the connections between these factors are also discussed. Methods Bioinformatics analysis was used to analyze the differential expression, survival prognosis, and correlation with pathways of GPX4 in gastric cancer,atrophic gastritis, and normal gastric mucosa. Thirty cases of normal gastric mucosa tissue, chronic atrophic gastritis, and gastric cancer tissue were collected for Western blot. In addition, archived pathological data were queried, and 30 embedded wax blocks of gastric cancer tissue, atrophic gastritis tissue, and adjacent normal tissue from 2022 to 2024 were retrieved. Immunohistochemical experiments were performed after sectioning. The protein expression levels of GPX4, HIF-1α, p-mTOR, and VEGF in tissues were detected by Western blot and immunohistochemistry, and the expression correlation between GPX4 and HIF-1α, p-mTOR, and VEGF in gastric cancer and precancerous lesions was analyzed. Results There were differences in the expression of GPX4 in normal and gastric cancer cases. It was highly expressed in gastric cancer, and patients in the high expression group had a short survival period. In immunohistochemistry and Western blot experiments, the expressions of GPX4, HIF-1α, p-mTOR, and VEGF in the gastric cancer group and atrophic gastritis group were higher than those in the adjacent normal tissue group, and the gastric cancer group was even higher than the atrophic gastritis group. These differences were statistically significant (P＜0.05). Spearman correlation analysis revealed that there was a significant connection and a positive correlation among GPX4, HIF-1α, p-mTOR, and VEGF (P＜0.05). Conclusion GPX4, HIF-1α, p-mTOR, and VEGF may jointly participate in the occurrence of gastric cancer through interaction, and their potential mechanism is related to the mammalian target of rapamycin (MTOR) signaling pathway. In particular, GPX4 can act as an inducement for gastric cancer and promote the development of cancer. Therefore, detecting GPX4 is of great significance for the early diagnosis, early treatment, and prevention of gastric cancer