Integrated multi-omics and experimental analysis identifies OPA1 as a prognostic biomarker and potential therapeutic target in glioma via mitochondrial destabilization and ROS-NF-κB signaling

Optic atrophy 1 (OPA1) is a dynamin-related GTPase located in the mitochondrial inner membrane and is essential for mitochondrial fusion, cristae integrity and energy metabolism. Emerging evidence indicates that OPA1 dysregulation contributes to tumorigenesis by altering mitochondrial dynamics, metabolic adaptability and apoptosis-related signaling. However, the biological function of OPA1 in glioma, particularly its immunological relevance and therapeutic implications, remains incompletely understood. Integrated multi-omics analyses were conducted using TCGA, CGGA, GEO, GTEx, CPTAC and HPA datasets to characterize OPA1 expression patterns, clinical associations and prognostic value in glioma and pan-cancer cohorts. Differential expression, functional enrichment (GO, KEGG, GSEA), immune infiltration (CIBERSORT, ssGSEA, TIMER), tumor mutational burden, microsatellite instability, DNA methylation, drug sensitivity (GDSC) and single-cell transcriptomic communication (CellChat) were systematically assessed. OPA1 protein expression was validated in clinical glioma tissues by Western blotting. Functional effects of OPA1 knockdown were evaluated in U251 and T98G cells using proliferation, migration and invasion assays. Mitochondrial membrane potential, intracellular ROS levels and NF-κB/p65 phosphorylation were analyzed. An orthotopic intracranial xenograft mouse model was used to examine the in vivo impact of OPA1 depletion on tumor growth and survival. OPA1 expression was significantly reduced in glioma relative to normal brain tissue and declined with increasing WHO grade. Higher OPA1 levels were enriched in IDH-mutant and 1p/19q-codeleted tumors and were associated with favorable clinicopathological features. OPA1 expression was also associated with distinct genomic landscapes, including differences in tumor mutational burden. Across multiple independent cohorts, elevated OPA1 expression consistently predicted improved overall and disease-specific survival.Functional analyses linked OPA1-associated genes to mitochondrial organization, oxidative phosphorylation, DNA repair, and immune regulation.Low OPA1 expression correlated with an immunosuppressive tumor microenvironment and increased immune-checkpoint expression, while OPA1 expression was also associated with distinct genomic features, including differences in tumor mutational burden. Single-cell analysis revealed distinct intercellular communication states associated with OPA1 expression.In vitro and in vivo experiments demonstrated that OPA1 loss induced mitochondrial dysfunction, increased ROS accumulation, enhanced NF-κB activation, and promoted malignant phenotypes and tumor progression. Rescue experiments using the ROS scavenger NAC partially reversed these effects, supporting the involvement of ROS-associated NF-κB signaling. OPA1 expression was also associated with differential predicted sensitivity to therapeutic agents. OPA1 functions as a protective factor in glioma and is associated with favorable clinical outcomes. By maintaining mitochondrial homeostasis and restraining ROS-associated NF-κB activation, OPA1 suppresses malignant progression of glioma. In addition, OPA1 expression is associated with distinct immune microenvironment characteristics, highlighting its potential as a prognostic biomarker and therapeutic target.