Diabetes impairs post-infarction cardiac repair by arresting macrophage pro-resolving programs through a pathological interferon-translation axis

Background Diabetes mellitus (DM) significantly worsens clinical outcomes following myocardial infarction (MI) by promoting chronic inflammation and maladaptive remodeling. However, the molecular checkpoints that arrest inflammation resolution in the diabetic heart remain elusive. Purpose We employed single-cell transcriptomics to determine how DM fundamentally rewires the innate immune response and identifies the mechanisms stalling the transition from inflammation to cardiac repair. Methods We utilized single-cell RNA sequencing (scRNA-seq) on infarcted myocardial tissue from healthy and DM mice. We mapped the transcriptional and cellular landscape of innate immune cells investigated cell type composition, gene expression programs, developmental trajectories, and cell-cell communication networks to pinpoint diabetes-specific alterations. Results We identified 13 myeloid clusters, including 7 macrophage (MΦ) and 3 neutrophil (Neut) subpopulations. In DM hearts, Neuts acted as pathological drivers, failing to reach a pro-resolving state. Crucially, DM induced a robust "pseudo-viral" transcriptional program in MΦ, driven by the cGAS-STING-Interferon axis and a profound STAT1-high/STAT3-low imbalance. The absence of a strong STAT3-associated transcriptional program in the diabetic MΦ groups suggests that the 'STAT-switch', the necessary transition from STAT1-mediated inflammation to STAT3-mediated resolution, is functionally impaired. This interferon-stimulated gene (ISG) signature (e.g., Ifi27l2a, Oas1a, Isg15) was universally coupled with the suppression of cytoplasmic translation and ribosomal proteins. This "IFN-Translation trade-off" created a molecular lockdown: while MΦ were locked into an antiviral-like inflammatory response, they actively arrested the protein synthesis required for repair factors and efferocytosis machinery. Trajectory analysis confirmed that this axis stalls MΦ maturation at a pro-inflammatory stage, redirecting the infarct microenvironment toward excessive fibrosis via dysregulated OSM-LIFR and Notch signaling. Conclusion DM hijacks the MΦ repair program by inducing a pathological "pseudo-viral" state that sacrifices the translational machinery necessary for tissue resolution. Targeting the cGAS-STING/IFN-Translation axis represents a promising therapeutic avenue to restore immune homeostasis and enhance outcomes in diabetic MI.Volcano plots of isolated cell clusters.Trajectory analysis of clusters.