Spatiotemporal Transcriptomics and Computational Modeling Reveal Stress Granule-Dependent Repression of Efferocytosis After Myocardial Infarction

Stress granules (SGs) are cytosolic ribonucleoprotein condensates that control translation of stress-responsive mRNAs and are increasingly linked to cardiovascular inflammation. How their spatiotemporal behaviour relates to efferocytosis during myocardial infarction (MI) remains poorly defined. We analysed 42 core SG genes and 144 efferocytosis-related genes across public multi-omics datasets: a mouse MI single-nucleus RNA sequencing and Visium spatial transcriptomic time series (GSE214611), an independent spatial cohort (GSE265828), the FinnGen R11 MI genome-wide association study, GTEx v10 tissue eQTLs, the LINCS L1000 perturbation compendium, and SG-fraction and G3bp1-knockout RNA-seq data (GSE263848 and GSE264134). Zone-stratified analysis showed coordinated upregulation of SG and efferocytosis programs in the infarct zone at day 3 (72 h; 10 SG and 32 efferocytosis genes) and day 7 (168 h; 11 SG and 34 efferocytosis genes), with a significant zone-by-time interaction for 312 genes, including G3bp1 and 36 efferocytosis genes. Macrophages carried most of the efferocytosis program, which was acutely suppressed at 1 h and recovered between 4 h and day 3. Macrophages with a high SG program showed consistent SG-gene upregulation at both cell and animal levels. In an independent SG-fraction RNA-seq dataset, 61 of 144 efferocytosis mRNAs, including Lrp1, Mertk and Mfge8, were enriched in SG fractions, supporting SG-mediated sequestration of efferocytosis transcripts. SG (ATXN2) and efferocytosis (APOE, LIPA) loci carried genome-wide significant MI signals, and all 42 SG genes were eQTL genes in the coronary artery. HSP90 inhibitors were associated with elevated SG-related expression scores in L1000 screening. These findings define a cross-cohort transcriptomic map of SG-efferocytosis programs in MI and support the hypothesis that ischaemic stress, SG assembly and efferocytosis regulation are temporally coordinated.