Purpose <p>Gliomas are the most common type of primary malignant brain tumor with high degree of malignancy and rapid progression, and patients often have complications such as epilepsy and cognitive impairment. Thus, identifying related therapeutic targets, prolonging patient survival time and improving patient quality of life are urgently needed. Recent studies have shown that glutamatergic neurons around tumors and glioma cells form synapses, neuron–glioma synapses (NGSs), which have electrophysiological properties and participate in the proliferation, infiltration and invasion of tumors. Therefore, we aimed to explore the molecular mechanisms underlying NGS formation.</p> Methods <p>We used bioinformatic analysis to screen for the expression of SPARCL1, which may play a role in promoting NGS formation, and we evaluated clinical samples through immunofluorescence, Western blot, and reverse transcriptase polymerase chain reaction (RT‒PCR) assays to validate the bioinformatic analysis results. Vitro neuron–glioma cell coculture model was established and allowed us to edit SPARCL1 expression in glioma cells, further allowing us to investigate the role of SPARCL1 in NGS formation.</p> Results <p>Bioinformatic analysis revealed that SPARCL1 is highly expressed in glioma cells and is associated with synaptogenesis. Clinical samples were evaluated to verify the bioinformatics results, and SPARCL1 was found to be highly distributed in the tumor peripheral region. In the vitro neuron–glioma cell coculture model, NGSs were clearly observed, and SPARCL1 overexpression promoted NGS formation.</p> Conclusion <p>Taken together, these findings suggest that SPARCL1 is one of the molecules that promotes NGS formation in the tumor peripheral region.</p>