Background <p>While the synaptic vesicle protein SYNGR4 has established roles in the pathobiology of motor neuron disease, its comprehensive oncogenic significance across diverse cancers, and its specific value as a clinical biomarker and therapeutic target in lung adenocarcinoma (LUAD), are entirely unexplored.</p> Methods <p>Our pan-cancer multi-omics analysis systematically assessed the expression, prognostic value, prognostic nomogram models, and clinical correlates of SYNGR4, investigated its DNA methylation, genetic alterations, and functional pathways (GO/KEGG/GSEA), and evaluated its associations with immune infiltration, immunotherapy response, and drug sensitivity across various cancer types. In addition, we performed qPCR, CCK-8, colony formation, EdU staining, and wound-healing analyses to elucidate the role of SYNGR4 in LUAD proliferation and migration.</p> Results <p>Our pan-cancer multi-omics results indicate that SYNGR4 is upregulated in multiple cancers and correlates with prognosis. Its expression was linked to DNA methylation, immune cell infiltration and improved responses to PD-1 blockade (nivolumab) and anti-PD-L1 therapy. SYNGR4 expression also showed positive correlations with sensitivity to MEK inhibitors (PD-0325901, Trametinib) and Docetaxel. Pathway analysis linked SYNGR4 to cell cycle progression and synthesis of DNA. In addition, knockdown of SYNGR4 via siRNA suppressed the proliferative and migratory capacities of LUAD cells in vitro.</p> Conclusion <p>This study establishes SYNGR4 as a novel prognostic biomarker in LUAD, thereby positioning it as a potential therapeutic target with clinical utility.</p>