Key Targets in Subacute Spinal Cord Injury Identified by Bioinformatics and Mendelian Randomization.

Abstract

This study leverages integrative bioinformatics and Mendelian randomization (MR) to uncover pivotal diagnostic biomarkers and therapeutic targets for subacute spinal cord injury (SCI), offering actionable insights for precision medicine. Transcriptomic data from rat models (GSE166009, GSE183591, GSE45006) were analyzed to identify differentially expressed genes, followed by enrichment and protein-protein interaction network analyses to pinpoint hub genes. Cross-species validation was performed in mouse (GSE249615), rat (GSE174549), and human (GSE151371) datasets. Receiver-operating characteristic curve analysis assessed diagnostic potential, and drug prediction identified therapeutic candidates. Causal relationships were validated using multivariable MR. A total of 640 differentially expressed genes were identified, enriched in critical pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells signaling, mitogen-activated protein kinase signaling, and extracellular matrix-receptor interactions. Nine hub genes were identified, 5 of which (toll-like receptor 4, intercellular adhesion molecule 1, cluster of differentiation 44, protein tyrosine phosphatase receptor type C, and allograft inflammatory factor 1) demonstrated robust cross-species expression patterns and diagnostic potential in human datasets. Drug prediction identified genistein, isoflavone, and dimethyl sulfoxide as promising candidates for modulating inflammation, reducing glial scarring, and promoting axonal repair. Key pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells signaling, extracellular matrix-receptor interaction, and hematopoietic cell lineage, were implicated in establishing a regenerative microenvironment. Multivariable MR analysis revealed intercellular adhesion molecule 1 as a protective factor in SCI, further supporting its therapeutic relevance. This study uncovers key molecular targets, pathways, and drugs for SCI recovery, providing a framework for precision therapeutics.