Integrative genomic analysis identifies key target genes and candidate drugs for spinal stenosis.

Abstract

Background: Spinal stenosis is a common pathological condition characterized by the narrowing of the spinal canal, contributing to substantial morbidity and imposing a significant socioeconomic burden. Despite its clinical importance, the genetic drivers and cellular mechanisms driving its progression remain inadequately understood, necessitating integrative approaches to identify therapeutic targets.

Methods: This study employed an integrative multi-omics strategy. Initially, summary-data-based Mendelian randomization was conducted using cis-expression quantitative trait loci data from 19,960 genes alongside spinal stenosis genome-wide association study data. Gene-gene interaction networks and colocalization analyses further refined candidate genes. Additionally, single-cell RNA sequencing of spinal tissues was performed to assess cellular enrichment, and molecular docking was employed to screened FDA-approved drugs against prioritized targets. Immunohistochemistry (IHC), Western blot (WB), and quantitative real-time PCR (qRT-PCR) were conducted using tissue samples and primary cells to validate the bioinformatics analysis results.

Results: SMR analysis identified 45 candidate target genes, which were further narrowed to three key genes including KAT5, TET2, and TAF10 through gene-gene interaction analysis and colocalization. Single-cell RNA sequencing revealed that these genes were predominantly enriched in chondrocytes and monocytes, implicating cellular cross-talk via the TGF-β1- (TGF-βR1 ++ TGF-βR2) pathway, a driver of fibrosis and ossification. Molecular docking identified six high-affinity compounds: Balsalazide and Eltrombopag for KAT5, Magnesium Citrate and Ferric Citrate for TET2, and Piracetam and Deferiprone for TAF10. The expression level of KAT5 and TET10 were both consistent with our SMR analysis in both tissues and primary cells.

Conclusion: These findings elucidate novel genetic and cellular mechanisms underlying spinal stenosis, highlighting the role of TGF-β pathway in disease progression. The identified compounds offer promising therapeutic interventions, bridging genomic discoveries to clinical applications and paving the way for targeted treatment strategies.