IRF7 links HK1-dependent histone lactylation to fibroblast activation and cardiac fibrosis [CUT&Tag]

In response to a myriad of stimuli quiescent resident cardiac fibroblasts undergo metabolic, morphological, and functional alterations to transition to myofibroblasts and mediate cardiac fibrosis. In the present study we investigated the contribution of interferon regulatory factor 7 (IRF7) to fibroblast activation and cardiac fibrosis. IRF7 knockdown in quiescent cardiac fibroblasts potentiated whereas IRF7 over-expression suppressed myofibroblast transition. Consistently, targeted deletion of IRF7 fibroblasts/myofibroblasts similarly exacerbated cardiac fibrosis and dampened heart function in animal models of heart failure. Integrated transcriptomic analysis uncovered Hexokinase 1 (Hk1) as a downstream target for IRF7. Congruently, genetic deletion or pharmaceutical inhibition of HK1 protected the mice from adverse cardiac remodeling. Mechanistically, HK1 contributed to cellular lactate pool to promote histone H3K9 lactylation thus licensing the transcription of pro-fibrogenic molecules. Finally, the relevance of the IRF7-HK1 axis was authenticated in human heart specimens. In conclusion, our data unveil a previously unrecognized IRF7-HK1 axis that contributes to metaboloepigenetic reprogramming of fibroblast activation and cardiac fibrosis. Targeting this axis might yield novel therapeutic solutions for the intervention of heart failure.