IRF7 links HK1-dependent histone lactylation to fibroblast activation and cardiac fibrosis

In response to various stimuli, quiescent resident cardiac fibroblasts undergo metabolic, morphological, and functional alterations, transitioning into myofibroblasts that mediate cardiac fibrosis. In the present study, we investigated the role of interferon regulatory factor 7 (IRF7) in fibroblast activation and cardiac fibrosis. Knockdown of IRF7 in quiescent cardiac fibroblasts potentiated myofibroblast transition, whereas overexpression of IRF7 suppressed it. Furthermore, targeted deletion of IRF7 in fibroblasts or myofibroblasts exacerbated cardiac fibrosis and impaired heart function in animal models of heart failure. Integrated transcriptomic analysis revealed hexokinase 1 (HK1) as an IRF7 downstream target. Consistently, genetic deletion or pharmacological inhibition of HK1 protected mice from adverse cardiac remodeling. Mechanistically, HK1 contributed to the cellular lactate pool, promoting histone H3K9 lactylation and enabling the transcription of pro-fibrogenic molecules. Finally, the relevance of the IRF7-HK1 axis was verified in human heart specimens. In conclusion, our data unveil an IRF7-HK1 axis that contributes to the metaboloepigenetic reprogramming of fibroblast activation and cardiac fibrosis. Targeting this axis may yield new therapeutic solutions for heart failure intervention.