TREM2 macrophages promote cardiac repair after myocardial infarction (MI) by reprogramming metabolism through SLC25A53. The study shows that macrophage-specific TREM2 deficiency worsens cardiac function and impairs post-MI repair. TREM2 expression in macrophages is increased after MI, with a peak on day 7. TREM2-deficient macrophages exhibit impaired efferocytosis, reduced SLC25A53 expression via the SYK-SMAD4 pathway, and decreased NAD+ transport into mitochondria, leading to TCA cycle disruption and increased itaconate production. In vitro experiments show that itaconate secreted by TREM2+ macrophages inhibits cardiomyocyte apoptosis and promotes fibroblast proliferation. Overexpression of TREM2 in macrophages improves cardiac function. The study reveals that TREM2 plays a critical role in MI by connecting efferocytosis to immune metabolism during cardiac repair. TREM2+ macrophages enhance NAD+ transport through SLC25A53, supporting TCA cycle function and reducing inflammation. Itaconate, a metabolic byproduct, promotes tissue repair by inhibiting cardiomyocyte apoptosis and stimulating fibroblast proliferation. The findings suggest that TREM2 is a promising therapeutic target for improving cardiac function after MI. The study provides insights into the mechanisms of TREM2 in macrophage function and cardiac repair, highlighting its potential in treating ischemic heart disease.TREM2 macrophages promote cardiac repair after myocardial infarction (MI) by reprogramming metabolism through SLC25A53. The study shows that macrophage-specific TREM2 deficiency worsens cardiac function and impairs post-MI repair. TREM2 expression in macrophages is increased after MI, with a peak on day 7. TREM2-deficient macrophages exhibit impaired efferocytosis, reduced SLC25A53 expression via the SYK-SMAD4 pathway, and decreased NAD+ transport into mitochondria, leading to TCA cycle disruption and increased itaconate production. In vitro experiments show that itaconate secreted by TREM2+ macrophages inhibits cardiomyocyte apoptosis and promotes fibroblast proliferation. Overexpression of TREM2 in macrophages improves cardiac function. The study reveals that TREM2 plays a critical role in MI by connecting efferocytosis to immune metabolism during cardiac repair. TREM2+ macrophages enhance NAD+ transport through SLC25A53, supporting TCA cycle function and reducing inflammation. Itaconate, a metabolic byproduct, promotes tissue repair by inhibiting cardiomyocyte apoptosis and stimulating fibroblast proliferation. The findings suggest that TREM2 is a promising therapeutic target for improving cardiac function after MI. The study provides insights into the mechanisms of TREM2 in macrophage function and cardiac repair, highlighting its potential in treating ischemic heart disease.