Objective <p>This study investigates the dual regulatory role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in macrophage polarization and its therapeutic potential for mitigating myocardial ischemia/reperfusion injury (MI/RI).</p> Methods <p>By integrating in vivo murine myocardial MI/RI models with macrophage-specific genetic manipulation and multi-omics analyses, including transcriptomics, proteomics, and energy metabolomics, we comprehensively investigated the cardio-protective effects, immune regulation, and potential mechanism of PGC1α. Mechanistic validations were performed using macrophage hypoxia/reoxygenation models combined with gain- and loss-of-function experiments to elucidate the molecular interactions within the PGC1α-mediated signaling network.</p> Results <p><?tk 4?>PGC1α emerged as a potential regulator of macrophage polarization through coordinated metabolic and protein regulation in MI/RI. It suppresses TLR4/NF-κB-driven inflammation via two prominent parallel pathways: (1) Metabolic control through SUCLG1/succinyl-CoA synthetase-mediated succinate generation; (2) negatively regulates protein by TRAF5 mRNA expression inhibition. This dual-axis regulation effectively dampens M1 macrophage polarization and pro-inflammatory cytokine storms. Furthermore, macrophage-specific PGC1α activation demonstrated cardio-protective effects by preserving cardiac function and reducing cardiomyocyte apoptosis.</p> Conclusion <p>Our findings established PGC1α as a potential regulator of macrophage polarization in MI/RI, bridging mitochondrial energy metabolism and protein expression with immune responses. The PGC1α-SUCLG1/succinate axis and PGC1α-TRAF5 axis unveil therapeutic targets and potential mechanisms for modulating inflammation in MI/RI. Future studies should focus on translating these mechanisms into clinical interventions through pharmacological PGC1α activation.</p>