Prognostic significance of SLC25A28 and its associations with mitochondrial metabolism and immune features in glioma

Background SLC25A28 encodes the mitochondrial iron transporter mitoferrin-2, but its prognostic relevance and biological associations in glioma remain incompletely characterized. We investigated its clinical significance and relationships with metabolic, ferroptosis-related and immune features across glioma cohorts. Methods SLC25-family genes were screened in CGGA and TCGA, followed by survival analysis and meta-analysis across nine GlioVis cohorts. Clinical Cox models, prognostic scores and grade/IDH subgroups were evaluated. Metabolic, immune and curated ferroptosis-related signatures were examined using clinically adjusted models, and immune-cell and checkpoint analyses underwent false-discovery-rate correction. SLC25A28 expression was assessed by qRT-PCR and Western blotting. Results Lower SLC25A28 expression was associated with unfavorable clinicopathological features and shorter overall survival (pooled hazard ratio, 1.91; 95% confidence interval, 1.46–2.50; I² = 84.9%). Exploratory analyses supported survival associations in both IDH-mutant and IDH-wild-type subgroups of CGGA and TCGA, although findings within glioblastoma varied. Positive oxidative-phosphorylation associations persisted after grade/IDH adjustment in both pooled cohorts; within glioblastoma, this association was supported in CGGA but not TCGA. Ferroptosis-related transcriptional associations were also detected, with consistent all-glioma WikiPathways results across sensitivity analyses in TCGA but scoring-method and cohort dependence in regulator signatures. Immune-cell differences survived correction for 10 of 22 populations in CGGA and 16 of 22 in TCGA, and three checkpoint genes showed positive correlations in both cohorts. qRT-PCR and Western blotting confirmed lower SLC25A28 expression in U87 and U251 cells than in normal human astrocytes. Conclusions SLC25A28 is a candidate prognostic biomarker associated with mitochondrial metabolism, ferroptosis-related transcriptional features and immune features in glioma. Multi-cohort survival evidence and clinically adjusted molecular associations support further evaluation of its prognostic and biological relevance. Subtype-specific clinical validation and functional investigations will help define its clinical utility and biological role.