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

Cardiac regeneration is limited in the adult mammalian heart due to restricted cardiomyocyte proliferation and persistent fibrosis. 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. Integration of CUT&RUN, chromatin accessibility, and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.