PGC1α alleviates M1 macrophage polarization through dual regulation of succinate metabolism and TRAF5 expression to mitigate TLR4/NF-κB-driven inflammatory cascades and myocardial ischemia/reperfusion injury

  • Inflamm Res. 2025 Nov 6;74(1):156. doi: 10.1007/s00011-025-02109-1.
Jiajie Leng  #  1  2  3  4 ,  Zhenrui Cao  #  1 ,  Letai Li  #  2 ,  Dingheng Hu  2  5 ,  Yuxiang Luo  1  6 ,  Bin Tu  1 ,  Xiaoying Cao  1 ,  Rui Tao  7  8 ,  Yingjiu Jiang  9 ,  Hongtao Tie  10
Affiliations
  • 1. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Chongqing Medical University, Chongqing, China.
  • 3. Weight Management Center, Bishan Hospital, Chonqqing University of Chinese Medicine, Chongqing, China.
  • 4. Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College of Chongqing Medical University, Chongqing, China.
  • 5. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6. Thoraxcenter, Department of Cardiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
  • 7. Weight Management Center, Bishan Hospital, Chonqqing University of Chinese Medicine, Chongqing, China. [email protected].
  • 8. Bishan Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 9. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 10. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 41196309 DOI: 10.1007/s00011-025-02109-1
Abstract

Objective: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
Immunometabolic crosstalk; M1 macrophage polarization; Myocardial ischemia–reperfusion injury; PGC1α; TLR4/NF-κB signaling.
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