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<p>Ischemic heart disease lacks optimal therapies targeting post-infarction inflammation and remodeling. The role of TCA cycle metabolites in modulating macrophage-driven cardiac inflammation remains unclear. This study hypothesized that AKG supplementation attenuates cardiac dysfunction by regulating macrophage activation via TCA cycle replenishment and FTO-dependent epigenetic mechanisms. Myocardial infarction was induced in male C57BL/6 mice and macrophage-specific FTO knockout mice via left anterior descending artery ligation. Mice received AKG supplementation. Techniques included echocardiography, histopathology, flow cytometry (quantifying Ly6C<sup>+</sup> macrophages), m6A-RIP-qPCR (assessing <i>Stat3</i> mRNA methylation), Western blotting (JAK1/STAT3 pathway), Seahorse metabolic analysis (BMDMs), and in vitro BMDM cultures. Data are mean ± SD; statistical significance (<i>p</i> &lt; 0.05) assessed by t-test/ANOVA. AKG restored TCA cycle flux and significantly reduced infarct size (<i>p</i> &lt; 0.01). It attenuated pro-inflammatory Ly6C<sup>+</sup> macrophage infiltration (<i>p</i> &lt; 0.05) versus controls. AKG required macrophage FTO expression, increasing STAT3 nuclear translocation (<i>p</i> &lt; 0.05) via FTO-mediated m6A demethylation of&#xa0;<i>Stat3</i>&#xa0;mRNA (<i>p</i> &lt; 0.01). This activated JAK1/STAT3 signaling, driving anti-inflammatory polarization and metabolic reprogramming (<i>p</i> &lt; 0.05). AKG supplementation attenuates post-infarction cardiac dysfunction primarily through FTO-mediated m6A demethylation of&#xa0;<i>Stat3</i>&#xa0;in macrophages, activating JAK1/STAT3 signaling to promote anti-inflammatory polarization and metabolic reprogramming. This defines a novel metabolite-epigenetic pathway (AKG-FTO-m6A-STAT3) for immunomodulation in ischemic injury, highlighting TCA cycle replenishment as a therapeutic strategy.</p>

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Alpha-ketoglutarate protects against myocardial infarction via FTO-mediated anti-inflammatory macrophage activation

  • 期刊论文

  • 发表日期：

    2025年8月16日

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  • Zhijun Lin,
  • Huan He,
  • Pinliang Chen,
  • Xin Dong,
  • Jialin Jiang,
  • Weiwei Huang,
  • Zigang Pan,
  • Zhuoji Guan,
  • Lu Lu,
  • Huan Li,
  • Yusheng Huang,
  • Zhong Wang,
  • Tong Luo,
  • Lingjun Wang,
  • Zixin Chen

摘要

Ischemic heart disease lacks optimal therapies targeting post-infarction inflammation and remodeling. The role of TCA cycle metabolites in modulating macrophage-driven cardiac inflammation remains unclear. This study hypothesized that AKG supplementation attenuates cardiac dysfunction by regulating macrophage activation via TCA cycle replenishment and FTO-dependent epigenetic mechanisms. Myocardial infarction was induced in male C57BL/6 mice and macrophage-specific FTO knockout mice via left anterior descending artery ligation. Mice received AKG supplementation. Techniques included echocardiography, histopathology, flow cytometry (quantifying Ly6C+ macrophages), m6A-RIP-qPCR (assessing Stat3 mRNA methylation), Western blotting (JAK1/STAT3 pathway), Seahorse metabolic analysis (BMDMs), and in vitro BMDM cultures. Data are mean ± SD; statistical significance (p < 0.05) assessed by t-test/ANOVA. AKG restored TCA cycle flux and significantly reduced infarct size (p < 0.01). It attenuated pro-inflammatory Ly6C+ macrophage infiltration (p < 0.05) versus controls. AKG required macrophage FTO expression, increasing STAT3 nuclear translocation (p < 0.05) via FTO-mediated m6A demethylation of Stat3 mRNA (p < 0.01). This activated JAK1/STAT3 signaling, driving anti-inflammatory polarization and metabolic reprogramming (p < 0.05). AKG supplementation attenuates post-infarction cardiac dysfunction primarily through FTO-mediated m6A demethylation of Stat3 in macrophages, activating JAK1/STAT3 signaling to promote anti-inflammatory polarization and metabolic reprogramming. This defines a novel metabolite-epigenetic pathway (AKG-FTO-m6A-STAT3) for immunomodulation in ischemic injury, highlighting TCA cycle replenishment as a therapeutic strategy.