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<p>Neural cell death is pivotal in the pathogenesis of spinal cord injury (SCI). Recent studies have revealed a spectrum of cell death modalities in SCI, extending beyond traditional apoptosis and necrosis. Yet, the interplay between these diverse forms of cell death in SCI remains elusive. Is simultaneous intervention in various forms of cell death necessary for formulating effective therapeutic strategies for post-SCI neural cell death? In this study, we analyzed transcriptomic data from a public database, focusing on murine spinal cord tissue after SCI. This analysis identified 33 differentially expressed death-related genes (DEDRGs) active in both the acute and subacute phases of SCI. Enrichment analysis using the KEGG revealed that 15 of these DEDRGs were enriched in pathways related to apoptosis (Mcl1, Ripk1, Ctsb, Fos, Ctsd, Jun, Akt3, Casp8, Mapk8), ferroptosis (Acsl3, Slc39a14, Slc3a2), necroptosis (Ripk1, Casp1, Casp8, Mapk8), and cellular senescence (Map2k3, Akt3, Mapk14). Subsequently, we established a murine SCI model and used WB and IF to confirm the presence of apoptosis, ferroptosis, necroptosis, and cellular senescence at 1, 3, and 7&#xa0;days after SCI. Furthermore, we utilized a single-cell database to elucidate the communication dynamics between immune and neural cells at these time intervals. This facilitated the identification of pivotal immune-related receptor-ligand pairs and their correlation with key DEDRGs. Our comprehensive analysis sheds light on the complex interplay between the immune cells and neural cells following SCI, underscoring the critical role of receptor-ligand pairs in neural-immune communication. Finally, we selectively targeted these 15 DEDRGs for gene ontology (GO) functional enrichment analysis. We then constructed an integrated mRNA-miRNA-lncRNA regulatory network and predicted potential pharmaceutical interventions. Notably, our findings suggest a prevalent co-occurrence and mutual influence among various cell death forms after SCI. Consequently, we advocate that therapeutic research strategies for SCI should encompass a multi-target approach, addressing several forms of cell death concurrently.</p>

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Integrated Bioinformatic Analysis and Experimental Validation for Crosstalk Among Various Forms of Cell Death in Spinal Cord Injury

  • 期刊论文

  • 发表日期：

    2025年12月17日

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  • Kuileung Tong,
  • Jianfeng Li,
  • Shan Li,
  • Shiming Li,
  • Guoliang Chen,
  • Shaoyu Liu,
  • Yuhang Li,
  • Ningning Chen,
  • Bin Liu

摘要

Neural cell death is pivotal in the pathogenesis of spinal cord injury (SCI). Recent studies have revealed a spectrum of cell death modalities in SCI, extending beyond traditional apoptosis and necrosis. Yet, the interplay between these diverse forms of cell death in SCI remains elusive. Is simultaneous intervention in various forms of cell death necessary for formulating effective therapeutic strategies for post-SCI neural cell death? In this study, we analyzed transcriptomic data from a public database, focusing on murine spinal cord tissue after SCI. This analysis identified 33 differentially expressed death-related genes (DEDRGs) active in both the acute and subacute phases of SCI. Enrichment analysis using the KEGG revealed that 15 of these DEDRGs were enriched in pathways related to apoptosis (Mcl1, Ripk1, Ctsb, Fos, Ctsd, Jun, Akt3, Casp8, Mapk8), ferroptosis (Acsl3, Slc39a14, Slc3a2), necroptosis (Ripk1, Casp1, Casp8, Mapk8), and cellular senescence (Map2k3, Akt3, Mapk14). Subsequently, we established a murine SCI model and used WB and IF to confirm the presence of apoptosis, ferroptosis, necroptosis, and cellular senescence at 1, 3, and 7 days after SCI. Furthermore, we utilized a single-cell database to elucidate the communication dynamics between immune and neural cells at these time intervals. This facilitated the identification of pivotal immune-related receptor-ligand pairs and their correlation with key DEDRGs. Our comprehensive analysis sheds light on the complex interplay between the immune cells and neural cells following SCI, underscoring the critical role of receptor-ligand pairs in neural-immune communication. Finally, we selectively targeted these 15 DEDRGs for gene ontology (GO) functional enrichment analysis. We then constructed an integrated mRNA-miRNA-lncRNA regulatory network and predicted potential pharmaceutical interventions. Notably, our findings suggest a prevalent co-occurrence and mutual influence among various cell death forms after SCI. Consequently, we advocate that therapeutic research strategies for SCI should encompass a multi-target approach, addressing several forms of cell death concurrently.