This study investigates the role of TREM2-expressing macrophages in myocardial infarction (MI) repair. The authors found that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Through RNA-seq, protein, and molecular docking analyses, they identified that TREM2-expressing macrophages decreased SLC25A53 transcription via the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria. This led to a breakpoint in the TCA cycle and increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages improved cardiac function. The study reveals a novel role for macrophage-specific TREM2 in MI, linking efferocytosis to immune metabolism during cardiac repair.This study investigates the role of TREM2-expressing macrophages in myocardial infarction (MI) repair. The authors found that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Through RNA-seq, protein, and molecular docking analyses, they identified that TREM2-expressing macrophages decreased SLC25A53 transcription via the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria. This led to a breakpoint in the TCA cycle and increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages improved cardiac function. The study reveals a novel role for macrophage-specific TREM2 in MI, linking efferocytosis to immune metabolism during cardiac repair.