Language

English

Publication Date

10-1-2026

Journal

Nature Cardiovascular Research

DOI

10.1038/s44161-026-00881-9

PMID

42806167

PMCID

PMC13658034

PubMedCentral® Posted Date

9-28-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Cardiac regeneration is limited in the adult mammalian heart because of restricted cardiomyocyte proliferation and persistent fibrosis. We previously demonstrated that transient pharmacological inhibition of succinate dehydrogenase (SDH) with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific Sdhb deletion dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function. SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked 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.

Keywords

Animals, Myocytes, Cardiac, Epigenesis, Genetic, Succinate Dehydrogenase, Cell Proliferation, Enzyme Inhibitors, Regeneration, Myocardial Infarction, Myofibroblasts, Fibrosis, Metabolic Reprogramming, Malonates, Chromatin Assembly and Disassembly, Mice, Knockout, Cells, Cultured, Energy Metabolism, Mice, Mitochondria, Heart, Disease model, Transcriptomics

Published Open-Access

yes

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