BackgroundPANoptosis is implicated in immunoinflammatory diseases, but its role in cerebral ischemia-reperfusion injury (CIRI) remains unclear.MethodsWe integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk RNA-sequencing (bulk RNA-seq) datasets to explore PANoptosis-related molecular signatures in ischemic stroke. scRNA-seq identified cellular subpopulations; ST revealed spatial expression. Multimodal intersection analysis (MIA) and high-dimensional weighted gene coexpression network analysis (hdWGCNA) detected PANoptosis-related differently expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA)-identified biomarkers were validated in GSE35338 and GSE137482. Analyses characterized spatiotemporal microglial dynamics. TNFRSF1A expression was validated by Western blot.ResultsNine stromal cell subtypes were mapped across 14 brain regions. Stroke-associated microglial clusters showed microglia-specific dysregulation of PANoptosis regulators (MCL1, TNFRSF1A, and STAT3), with TNFRSF1A upregulated in the ischemic core. Altered intercellular communication via SPP1, MIF, FN1, and TNF pathways were observed. Pseudotime analysis revealed dynamic microglial reprogramming. TNFRSF1A showed time-dependent upregulation post-CIRI, validated at the protein level.ConclusionsTNFRSF1A acts as a key PANoptosis-related biomarker and suggests microglial subclusters as therapeutic targets in ischemic stroke.