Ischemic Postconditioning Regulates New Cell Death Mechanisms in Stroke: Disulfidptosis.

BACKGROUND AND OBJECTIVE

Stroke poses a critical health issue without effective neuroprotection. We explore ischemic postconditioning's (IPostC) potential to mitigate stroke-induced brain injury, focusing on its interaction with disulfidptosis, a novel cell death pathway marked by protein disulfide accumulation. We aim to clarify IPostC's protective mechanisms against stroke through gene sequencing and experimental analysis in mice.

METHODS

Through our initial investigation, we identified 27 disulfidptosis-related genes (DRGs) and uncovered their interactions. Additionally, differential gene analysis revealed 11 potential candidate genes that are linked to disulfidptosis, stroke, and IPostC. Our comprehensive study employed various analytical approaches, including machine learning, functional enrichment analysis, immune analysis, drug sensitivity analysis, and qPCR experiments, to gain insights into the molecular mechanisms underlying these processes.

RESULTS

Our study identified and expanded the list of disulfidptosis-related genes (DRGs) critical to stroke, revealing key genes and their interactions. Through bioinformatics analyses, including PCA, UMAP, and differential gene expression, we were able to differentiate the effects of stroke from those of postconditioning, identifying () as a key gene of interest. GSEA highlighted 's involvement in protective pathways against ischemic damage, while its correlations with various proteins suggest a broad impact on stroke pathology. Constructing a ceRNA network and analyzing drug sensitivities, we explored 's regulatory mechanisms, proposing novel therapeutic avenues. Additionally, our immune infiltration analysis linked to key immune cells, underscoring its dual role in stroke progression and recovery. is identified as a key target in ischemic stroke based on colocalization analysis, which revealed that and ischemic stroke share the causal variant rs17522918. The causal relationship between -related methylation sites (cg02631906 and cg08483560) and the risk of ischemic stroke further validates as a crucial target.

CONCLUSIONS

These results suggest that the DRGs are interconnected with various cell death pathways and immune processes, potentially contributing to IPostC regulating cell death mechanisms in stroke.