Background and Aims F-box protein (FBP) family member F-box only protein 43 (FBXO43) is highly expressed in digestive system tumors such as liver cancer and colorectal cancer, promoting malignant progression of tumors. Research has shown that FBXO43 promotes the degradation of p53, exerting oncogenic functions. Therefore, this study was conducted to further explore the expression of FBXO43 in gastric cancer and its role and related mechanisms in the malignant progression of gastric cancer.Methods Based on online databases such as TCGA, GTEx, and Kaplan-Meier Plotter, the expression of FBXO43 in gastric cancer tissues and its correlation with the prognosis of gastric cancer patients were analyzed. Western blot and qPCR were used to detect the expression levels of FBXO43 in gastric cancer cells and normal gastric mucosal epithelial cells. Immunohistochemical staining was performed to detect the protein levels of FBXO43 in gastric cancer and adjacent tissues. Specific small interfering RNA molecules targeting FBXO43 and p53 (siFBXO43 and sip53) were transfected into HGC27 and MGC803 cells to knock down the expression of FBXO43 and p53 alone or simultaneously. Cell Counting Kit-8 (CCK8) assay, colony formation assay, Transwell invasion and migration assays were used to detect the effects of FBXO43 knockdown on the proliferation, invasion, and migration abilities of gastric cancer cells. Co-immunoprecipitation (Co-IP) was used to detect the interaction between FBXO43 and p53, as well as the total ubiquitination level of p53 after FBXO43 knockdown.Results TCGA and GTEx data showed that the expression level of FBXO43 was significantly upregulated in gastric cancer (both P<0.05). Kaplan-Meier Plotter data showed that high expression of FBXO43 was significantly associated with shortened overall survival (HR=1.39, 95% CI=1.09-1.78, P=0.007 6), progression-free survival (HR=1.35, 95% CI=1.04-1.76, P=0.023), and post-progression survival (HR=1.6, 95% CI=1.18-2.17, P=0.002 1) of gastric cancer patients. Western blot, qPCR, and immunohistochemistry results showed that FBXO43 was upregulated in gastric cancer cells and tissues, and the protein level of FBXO43 was significantly associated with tumor size, distant metastasis, and TNM stage of gastric cancer patients (all P<0.05). CCK8 assay, colony formation assay, Transwell invasion, and migration assays showed that knockdown of FBXO43 expression significantly inhibited the proliferation, invasion, and migration abilities of gastric cancer cells (all P<0.05). Knockdown of FBXO43 expression upregulated the protein level of p53. Co-IP results showed that FBXO43 and p53 could co-immunoprecipitate with each other, and knockdown of FBXO43 significantly increased the total ubiquitination level of p53. Functional experiments showed that simultaneous knockdown of p53 antagonized the inhibitory effects of FBXO43 knockdown on the proliferation, invasion, and migration abilities of gastric cancer cells, restoring the malignant phenotype of gastric cancer cells in vitro (all P<0.05).Conclusion FBXO43 is highly expressed in gastric cancer and is closely associated with poor prognosis in gastric cancer patients. The mechanism of action of FBXO43 may involve interaction with p53, promoting p53 ubiquitination and degradation, thereby promoting the malignant progression of gastric cancer. FBXO43 is expected to become a therapeutic target for gastric cancer.