Signal Transduct Target Ther. 2026 May 14;11(1):179. doi: 10.1038/s41392-026-02656-x.
ABSTRACT
Heart disease is characterized by stress-induced endoreplication preceding pathological cardiomyocyte overgrowth, yet the upstream regulatory mechanisms linking tissue hypoxia to aberrant cellular growth remain incompletely defined. Here, we identify cardiac hypoxia as a key determinant of endoreplication through activation of a hypoxia-inducible factor-1 alpha-microRNA regulatory axis that converges on mitochondrial energetic control. We show that stress-induced activation of hypoxia-inducible factor-1 alpha drives transcriptional induction of microRNA-27b-5p, which directly represses the ATP synthase subunit ATP5A1, resulting in impaired mitochondrial ATP synthesis and accumulation of intra-mitochondrial ADP. Elevated ADP serves as a rate-limiting cofactor for one-carbon metabolism, promoting formate production and de novo purine biosynthesis, thereby enabling pathological endoreplication and cardiomyocyte hypertrophic growth. Genetic gain- and loss-of-function studies targeting hypoxia-inducible factor-1 alpha, microRNA-27b, and ATP5A1 across multiple mouse models of cardiac stress, together with correlative analyses of human cardiac biopsies, establish a conserved and causal relationship between dysregulated mitochondrial energetics and pathological cardiac remodeling. Inhibition of microRNA-27b-5p attenuates established cardiac hypertrophy, improves cardiac function, and suppresses stress-induced multinucleation in vivo. Leveraging this mechanistic insight, we identify the clinically approved antifolate compound methotrexate as an effective inhibitor of stress-induced cardiac endoreplication and pathological hypertrophy in preclinical models. Collectively, these findings define a druggable hypoxia-driven metabolic pathway linking mitochondrial ATP homeostasis to pathological cardiomyocyte growth and suggest therapeutic opportunities for targeting maladaptive cardiac remodeling.
PMID:42135278 | DOI:10.1038/s41392-026-02656-x