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SH3 domain-binding glutamic acid-rich protein-like 3 (SH3BGRL3) is involved in several human cancers. However, its relationship with gastric cancer (GC) remains elusive. Multiple online bioinformatic tools were used to evaluate the messenger (m)RNA expression levels of SH3BGRL3 in GC using data from The Cancer Genome Atlas and Gene Expression Omnibus databases. Reverse transcription-quantitative PCR and tissue microarray-based immunohistochemistry were performed to assess SH3BGRL3 expression in relation to clinicopathological parameters and outcomes in patients with GC. Significant differentially expressed genes (DEGs) of SH3BGRL3 were enriched and visualized. Furthermore, associations between the expression of SH3BGRL3 and the infiltration of immune cells were explored. SH3BGRL3 exhibited aberrant expression in tumor tissues compared with adjacent normal tissues at the mRNA and protein expression levels, especially in Epstein-Barr virus-negative GC (EBVnGC). Higher SH3BGRL3 expression was significantly associated with increasing tumor-node-metastasis staging, tumor budding, perineural invasion, EGFR expression, and a notably higher preoperative blood glucose concentration in clinical specimens. Multivariate analysis revealed that higher SH3BGRL3 expression was an independent adverse prognostic factor for the overall survival of patients with EBVnGC (hazard ratio, 1.666; P=0.018). Furthermore, the stratified analysis revealed that the SH3BGRL3 phenotype could help to refine prognosis in patients. The C-index of the nomogram was 0.740 when combining SH3BGRL3 with other clinicopathological parameters, which indicated a good model for clinical follow-up decisions. Gene functional enrichment analysis also revealed that the DEGs of SH3BGRL3 were mainly enriched in regulating ATP metabolism, ATP synthesis, oxidative phosphorylation and the electron transport chain in GC. Moreover, a higher SH3BGRL3 expression was significantly positively correlated with the infiltrating macrophages in GC. In conclusion, SH3BGRL3 is upregulated in GC, particularly in EBVnGC. Higher SH3BGRL3 expression is closely associated with hyperglycemia and poor outcomes in patients with EBVnGC, suggesting its potential as a biomarker and prognostic predictor. [ABSTRACT FROM AUTHOR]