CD9 expression rivals IDH mutation as a prognostic marker in glioma: a novel nomogram approach.

PURPOSE

Glioma remains a lethal malignancy with limited prognostic biomarkers. This study evaluates the prognostic significance and functional mechanisms of tetraspanin CD9 in glioma to establish its clinical relevance and identify therapeutic strategies.

METHODS

Multi-omics analyses were performed using 1,033 glioma samples from TCGA and CGGA cohorts. A CD9-integrated nomogram was developed via Cox regression. Two-sample Mendelian randomization (MR) assessed the causal link between CD9 expression and glioma risk using IVW, MR-Egger, and WM methods. KEGG enrichment analysis identified biological pathways. Single-cell RNA sequencing from 20 glioblastoma cases was analyzed using CellChat and Monocle3 to explore CD9-mediated cell communication and lineage transitions. Protein-protein interaction (PPI) networks were constructed via STRING and GeneMANIA, and drug predictions were performed using DsigDB.

RESULTS

CD9 overexpression was an independent predictor of poor survival (HR = 1.28, 95% CI 1.03-1.58). The CD9-based nomogram showed high prognostic accuracy (CGGA: C-index = 0.805 ± 0.01, TCGA: C-index = 0.859 ± 0.02). MR confirmed a causal association between CD9 and glioma risk (IVW OR = 1.33,  < 0.05) with no horizontal pleiotropy. CD9 regulated glioma progression via calcium signaling and synaptic pathways, interacting with ITGB1 and CD81. Single-cell analysis revealed CD9-driven NPC-to-OPC transdifferentiation, linked to tumor proliferation. Emetine was identified as a potential CD9-targeting drug.

CONCLUSION

CD9 is a prognostic biomarker in glioma, with causal evidence linking its overexpression to tumor development. Its integration into risk models enhances prognostic precision, while drug screening highlights emetine as a potential therapy.