A Metabolic-Epigenetic Switch Governs Heart Regeneration Following Succinate Dehydrogenase Inhibition

Cardiac regeneration remains limited in the adult mammalian heart, due to restricted cardiomyocyte proliferative capacity and persistent fibrotic remodeling following injury. We previously demonstrated that malonate, a competitive inhibitor of succinate dehydrogenase (SDH), promotes cardiomyocyte proliferation and functional regeneration after myocardial infarction (MI). Here, we define the mechanisms underlying this regenerative response using integrated single-nucleus (sn) RNA-seq and ATAC-seq, revealing widespread transcriptional and epigenetic reprogramming that drives adult cardiomyocyte proliferation and suppresses profibrotic gene expression in the injured heart. To dissect the cell-specific roles of SDH inhibition, we generated conditional deletions of the SDH subunit gene Sdhb in cardiomyocytes and myofibroblasts. Cardiomyocyte-specific Sdhb deletion enhanced cardiomyocyte proliferation both at baseline and post-MI; however, this sustained proliferative response occurred at the expense of restored cardiac function. In contrast, myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrotic remodeling, resulting in improved cardiac function following MI. Mechanistically, SDH inhibition promoted reductive mitochondrial metabolism in cardiomyocytes and triggered epigenetic remodeling marked by reduced H3K4me3 and H3K27me3, establishing a metabolic-epigenetic switch that activates a multicellular cardiac regeneration program in the adult heart. To identify bona fide regulatory targets of SDH inhibition, we integrated CUT&RUN profiling of H3K4me3 and H3K27me3 with chromatin accessibility and transcriptional data, confirming that key genes upregulated in malonate-treated cardiomyocytes are marked by concordant histone modifications and open chromatin at their regulatory regions. Together, these findings identify SDH as a central regulator of cardiac regeneration through distinct cell-specific and epigenetic mechanisms, and establish metabolic targeting of SDH as a promising strategy for heart regeneration.