Accumulation of newly synthesized docosahexaenoic acid plays an essential role in heart regeneration.

Adult zebrafish and neonatal mice can fully regenerate their hearts after partial amputation through the proliferation of preexisting cardiomyocytes (CMs). However, the adult mammalian heart has limited regenerative capability following cardiac damage. The reason for this phenomenon remains elusive. Here, we find that docosahexaenoic acid (DHA) is accumulated only in the injured hearts of zebrafish and neonatal mice, but not of adult mice, which coincides with the upregulation of DHA synthesis genes in CMs, fibroblasts, and macrophages near the injury areas. Inhibition of Fads2, a DHA synthesis enzyme, impairs heart regeneration in both zebrafish and neonatal mice. Injection of DHA remodels the transcriptome from injury response to regeneration response and improves cardiac function in adult mice after myocardial infarction. Interestingly, DHA facilitates CM proliferation but inhibits fibrosis and inflammation. Mechanistically, only DHA, but not oleic acid (OA), can trigger the peroxisome proliferator-activated receptor d (PPARD) to bind to the promoter regions of heart regeneration-related genes, such as Mef2d, Phlda3, and Txndc5, to regulate their expression. Molecular docking, molecular dynamics simulations, and mutagenesis experiments suggest that DHA binds to PPARD in a distinct manner compared to OA, which may help explain their differing abilities to influence the expression of heart regeneration genes. Our findings demonstrate that the DHA signal plays an essential and evolutionarily conserved role in heart regeneration and provide a therapeutic potential for myocardial infarction.