Sphingolipid metabolism-related genes as key regulatory hubs in white-smoke inhalation induced lung injury
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Objective
White smoke inhalation injury (WSI) causes severe acute lung damage with no specific therapy currently available. Sphingolipid metabolism is implicated in pulmonary inflammation, but its transcriptional regulatory landscape in WSI remains unexplored. This study aimed to identify key sphingolipid metabolism-related genes and evaluate their regulatory roles and therapeutic potential in WSI.
Methods
We established a rat model of WSI and performed integrated bulk RNA-sequencing, weighted gene co-expression network analysis (WGCNA), and single-cell RNA sequencing (scRNA-seq) to screen for differentially expressed sphingolipid metabolism-related genes (DE-SRGs). Protein-protein interaction (PPI) network with four centrality algorithms was used to prioritize hub genes. In silico gene knockout and molecular docking were conducted to assess regulatory functions and identify potential drug candidates.
Results
We identified 22 DE-SRGs that were predominantly enriched in DNA replication and cell cycle pathways rather than canonical sphingolipid metabolic processes. PPI consensus prioritized three hub genes— Top2a , Ttk , and Ccna2 —with Top2a exhibiting the highest expression in epithelial cells and significant downregulation after smoke exposure. ScRNA-seq revealed immune cell infiltration and epithelial differentiation trajectories. Virtual knockout showed that Top2a depletion affected the largest transcriptomic fraction (∼0.4%) and was enriched in lysosome biogenesis, innate immunity, phagocytosis, and lipid catabolism. Molecular docking identified thalidomide as a high-affinity ligand for Top2a (Vina score: −8.5 kcal/mol).
Conclusion
Our multi-omics integrative framework identifies Top2a as a central regulatory hub linking sphingolipid-associated inflammation to epithelial responses in WSI, and nominates thalidomide as a potential drug-repurposing candidate. These findings provide prioritized targets for future translational investigation.
