Abstract

Introduction Glioma is a highly aggressive primary brain tumor. To identify novel prognostic biomolecules and potential therapeutic targets, we investigated Aspartate betahydroxylase domain-containing protein 1 (ASPHD1), encoded by the ASPHD1 gene and predicted to function as a Fe (II)/2-oxoglutarate–dependent dioxygenase involved in peptide amino-acid modification. ASPHD1 has not previously been characterized in glioma. Methods We assessed its expression and prognostic value using transcriptomic data from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Chinese Glioma Genome Atlas (CGGA). Co-expressed gene enrichment and DNA-methylation analyses were performed, and associations between ASPHD1 expression and overall survival (OS) were evaluated. Gene Ontology and KEGG analyses of ASPHD1 coexpressed genes indicated enrichment in synaptic signaling, ion-channel activity, and calcium-signaling pathways, suggesting a link with neuronal and synaptic function. Results ASPHD1 expression showed a pronounced inverse correlation with WHO grade, and higher ASPHD1 expression was associated with prolonged OS; multivariable Cox models identified low ASPHD1 as an independent adverse prognostic factor. Pan-cancer analysis further revealed that higher ASPHD1 expression was associated with longer OS in skin cutaneous melanoma (SKCM), uveal melanoma (UVM), and mesothelioma (MESO). In glioma cell lines, ASPHD1 overexpression suppressed proliferation, migration, and invasion in vitro, and inhibited tumor growth in a subcutaneous U87 xenograft model. ASPHD1 overexpression also upregulated neuronal differentiation–related genes, produced more negative resting membrane potentials on whole-cell patch-clamp recordings, enhanced depolarization-evoked Ca 2+ transients on calcium imaging, and increased NeuN protein expression. Discussion Together, these findings identify ASPHD1 as a favorable prognostic biomarker in glioma and suggest that high ASPHD1 expression restra