A Metabolic-Epigenetic Switch Governs Multicellular Cardiac Repair Following Succinate Dehydrogenase Inhibition

We previously demonstrated that transient pharmacological inhibition of succinate dehydrogenase (SDH) with malonate promotes cardiac regeneration after myocardial infarction (MI). Here, integrated single-nucleus RNA-seq and ATAC-seq reveal multicellular transcriptional and epigenetic reprogramming underlying this response.

Cell-specific Sdhb deletion dissected distinct contributions of SDH inhibition: cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-MI function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function. SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3- and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts.