BackgroundCisplatin (CDDP) is of importance in cancer treatment and widely used in advanced gastric cancer (GC). However, its clinical usage is limited due to its resistance, and the regulatory mechanism of CDDP resistance in GC has not yet been fully elucidated. In this study, we first conducted a comprehensive study to investigate the role of MFAP2 through bioinformatics analysis.MethodsThe Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were applied to downloadgene expression data and clinicopathologic data, and the differentially expressed genes (DEGs) were further analyzed. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and survival analysis were conducted. Furthermore, according to the clinicopathological characteristics of TCGA, clinical correlation analysis was conducted, and a receiver operating characteristic curve (ROC) was plotted.ResultsWe revealed thatFAP,INHBAandMFAP2were good diagnostic factors of GC. However, the mechanism of MFAP2 in GC remains elusive, especially in the aspect of chemotherapy resistance. We developed the CDDP-resistant cell line, and found that MFAP2 was upregulated in CDDP-resistant cells, and MFAP2-knockdown improved CDDP sensitivity. Finally, we found that MFAP2 enhanced CDDP resistance by inducing autophagy in drug-resistant cell lines.ConclusionsThe above results suggested that MFAP2 could affect the chemotherapy resistance by altering the level of autophagy in GC patients as a potential therapeutic target.