Characterization of Ferroptosis-Related Molecular Subtypes with Immune Infiltrations in Neuropathic Pain

Abstract

Background Neuropathic pain (NP) caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition that has a major impact on quality of life. However, NP pathogenesis remains unclear. The purpose of this study was to identify differentially expressed genes (DEGs) and specific and meaningful gene targets for the diagnosis and treatment of NP. Methods Data from rat spinal nerve ligations and the sham group were downloaded from the Gene Expression Omnibus (GEO) database. Based on the single-sample gene set enrichment analysis (ssGSEA) method, 29 immune gene sets were identified in each sample, and these samples were correlated with the immune infiltration phenotype. LASSO regression modeling was used to screen key genes to identify diagnostic gene markers. According to GSEA and GSVA, NP is concentrated in a large number of immune-related pathways and genes. Additionally, we used the DGIdb database and correlation test to construct gene-drug and transcription factor interaction networks for differentially expressed genes relevant to NP-related ferroptosis. We used WGCNA to identify gene co-expression modules of NP, and explored the relationship between gene networks and phenotypes. Finally, we crossed core genes with diagnostic markers and analyzed gene correlation with molecular subtypes and immune cells. Results We identified 224 DEGs, including 191 upregulated genes and 33 downregulated genes. APC co-stimulation, CCR, cytolytic activity, humid-promoting, neutrophils, NK cells, and RGS4, CXCL2, DRD4 and other 7 genes related to ferroptosis were involved in NP development. Key genes of RGS4 and HIF−1 signaling pathway were screened. Conclusion This study contributes to our understanding of the neuroimmune mechanism of neuropathic pain, provides a reference for NP biomarkers and drug targets. Ferroptosis may be the next research direction to explore NP mechanism.

Diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease

“…GSEA is used to evaluate the distribution trend of genes from a predefined gene set in the gene list ranked with phenotypic relevance, to judge its contribution to phenotype 21 . We used the R packages limma, org.…”

Ferroptosis: a new regulatory mechanism in neuropathic pain

“…It has been shown that reactive oxygen species (ROS) and oxidative stress are involved in the development of NP. Under normal physiological conditions, intracellular antioxidants are in dynamic balance with intracellular ROS ( Bi et al, 2022 ). When mitochondrial damage occurs, ROS production is significantly higher compared to normal physiological levels.…”

“…When mitochondrial damage occurs, ROS production is significantly higher compared to normal physiological levels. And endogenous antioxidants are severely depleted, resulting in a disruption of the balance, leading to intracellular oxidative stress ( Bi et al, 2022 ). Reactive oxygen species scavengers can alleviate NP.…”

“…Non-programmed cell death is cell death that is directly caused by physical and chemical factors and cannot be regulated. Programmed cell death, on the other hand, is modifiable ( Bi et al, 2022 ). Ferroptosis as new programmed cell death is morphologically manifested mainly by the rupture of the outer mitochondrial membrane, the increase in the density of the inner mitochondrial membrane, and the reduction or disappearance of the mitochondrial cristae ( Xie et al, 2016 ).…”