Basic Res Cardiol. 2025 Aug 16. doi: 10.1007/s00395-025-01135-8. Online ahead of print.
ABSTRACT
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.
PMID:40817969 | DOI:10.1007/s00395-025-01135-8
