Cross-linked genes analysis of programmed cell death and network pharmacological validation after spinal cord injury

Programmed cell death (PCD), which describes cell death regulated by a sequence of gene expression events, strongly impacts the prognosis of spinal cord injury (SCI). Nevertheless, the connections between the various PCD types and the cross-linked genes regulate that these types of cell death in SCI remain unclear. This study sought to identify and investigate the key genes connections that regulated PCD in SCI. First, differentially expressed miRNAs (DEmiRNAs) and differentially expressed genes (DEGs) associated with SCI were extracted from the Gene Expression Omnibus (GEO) database. A total of 146 PCD-related DEGs and 187 DEmiRNAs were identified. A PCD-related miRNA‒mRNA interaction network was then constructed, comprising 35 overlapping genes and 37 overlapping miRNAs. Using protein‒protein interaction (PPI) network analysis and weighted gene co-expression network analysis (WGCNA), seven key cross-linked genes were identified. These genes were validated in an animal model of SCI, with further confirmation of their expression through peripheral blood sample sequencing data from human SCI patients and experimental animal research. Additionally, pharmacological prediction identified BAY 11-7082 as a potential modulator of PCD for SCI repair. The therapeutic efficacy of BAY 11-7082 was subsequently confirmed in a rat model of SCI. This study unveiled cross-linked genes and miRNA‒mRNA networks critical to PCD in SCI through integrative bioinformatics analyses. Furthermore, it identified BAY 11-7082 as a promising therapeutic agent for modulating PCD, offering a novel strategy for spinal cord injury repair.