Identification of genes associated with disulfidptosis in the subacute phase of spinal cord injury and analysis of potential therapeutic targets.

INTRODUCTION: Disulfidptosis, a recently identified form of regulated cell death, plays a potential role in secondary injury following spinal cord injury (SCI). However, its regulatory mechanisms and therapeutic targets during the subacute phase remain unclear. This study aimed to systematically identify core disulfidptosis-related genes (DRGs) in subacute SCI and explore potential diagnostic biomarkers and therapeutic compounds. METHODS: Two GEO datasets-GSE151371 and GSE45006 were analyzed. Differentially expressed genes (DEGs) were intersected with known DRGs to obtain disulfidptosis-related DEGs (DE-DRGs). Immune cell infiltration was assessed using CIBERSORT, while small-molecule prediction and molecular docking identified candidate compounds. Key diagnostic genes were screened by random forest and LASSO algorithms and validated via receiver operating characteristic (ROC) analysis. A protein-protein interaction (PPI) network was constructed, and Mfuzz clustering analyzed temporal expression patterns. Immunofluorescence staining of rat SCI sections validated IQGAP1 expression and cellular localization by co-labeling with cell-type markers and quantifying co-localization coefficients. RESULTS: A total of 6,948 DEGs were obtained, among which 8 overlapped with known DRGs. IQGAP1 was significantly upregulated in SCI samples, positively correlated with neutrophil infiltration, and located at the core of the PPI network. It was identified as a key diagnostic gene by both machine learning algorithms, showing a high diagnostic accuracy (AUC = 0.974). Molecular docking indicated a strong binding affinity between IQGAP1 and small molecules such as vitamin E (binding energy < -7.0 kcal/mol). Time-series clustering revealed sustained upregulation of IQGAP1 from day 7 onward in the subacute phase. Functional enrichment analyses (GO, KEGG, GSVA, and GSEA) implicated IQGAP1 in cytoskeleton remodeling, immune regulation, and metabolic reprogramming. Immunofluorescence in SCI rat models confirmed consistent spatial expression patterns. DISCUSSION: IQGAP1 was identified as a central regulator of disulfidptosis during the subacute phase of SCI, exhibiting strong diagnostic and therapeutic potential. Its association with immune infiltration and metabolic remodeling suggests that targeting IQGAP1 may offer novel strategies for mitigating secondary injury in SCI.