Steroid hormone-related transcriptomic signatures identify key molecular drivers of primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a complex genetic disorder leading to irreversible vision loss, and emerging evidence indicates that steroid hormones (SHs) are elevated in POAG patients, suggesting a potential regulatory role in disease progression. In this study, two publicly available Gene Expression Omnibus (GEO) transcriptomic datasets from human trabecular meshwork (TM) tissue (GSE27276) and non-human macaque (Macaca mulatta) TM single-cell RNA sequencing (scRNA-seq) (GSE231749) were analyzed. Differentially expressed genes (DEGs) were identified using the limma package, and 603 DEGs were intersected with a curated set of 1,453 SH-related genes obtained from GeneCards to derive SH-related DEGs. A random forest model then identified six hub genes that demonstrate strong diagnostic performance. scRNA-seq showed that HSPA8 and PTGDS were significantly upregulated in POAG and localized to TM-related stromal and smooth muscle-like cell clusters, with pathway enrichment indicating involvement in steroid hormone signaling, extracellular matrix (ECM) regulation, and prostaglandin biosynthesis. Further validation is still needed in clinical aqueous humor and TM tissue samples to determine whether the abnormal expression of HSPA8 and PTGDS in TM tissue is consistent with the diagnosis of POAG, and to evaluate their correlation with disease progression. Predicted drug-gene interaction analysis, including VER-155008 for HSPA8 and AT-56 for PTGDS, identifies potential therapeutic candidates. Overall, the integrated bulk and single-cell transcriptomic analysis defines SH-related molecular signatures in POAG and highlights HSPA8 and PTGDS as potential therapeutic and prognostic biomarkers.