In the relentless quest to understand the molecular underpinnings of heart regeneration, a groundbreaking study has emerged from the laboratories of Zhejiang University, shedding new light on the role of lipid signaling in cardiac repair. The enigmatic disparity in cardiac regenerative capacities among species—where adult zebrafish and neonatal mice demonstrate robust heart regeneration, contrasted starkly by the limited ability of adult mammals—has long puzzled cardiovascular researchers. Now, the discovery of docosahexaenoic acid’s (DHA) pivotal role offers a promising avenue that may revolutionize regenerative medicine.
Cardiac regeneration in adult zebrafish and neonatal mice occurs through the proliferation of pre-existing cardiomyocytes (CMs), enabling these organisms to restore heart function even after substantial tissue loss. Yet, adult mammals exhibit a starkly diminished regenerative response, often resulting in deleterious fibrotic scarring and heart failure. The molecular mechanisms driving this difference have remained elusive, until now. The recent study reveals that DHA, a long-chain omega-3 polyunsaturated fatty acid, accumulates uniquely within the injury sites of zebrafish and neonatal mouse hearts but conspicuously not in adult mouse hearts following myocardial injury.
Investigators meticulously mapped the spatial and temporal distribution of DHA, intertwining lipidomic profiles with gene expression analyses. This synthesis unveiled an upregulation of genes responsible for endogenous DHA biosynthesis, including the rate-limiting enzyme fatty acid desaturase 2 (Fads2), localized primarily to cardiomyocytes, fibroblasts, and macrophages surrounding the damaged myocardium. Intriguingly, interference with Fads2 expression through targeted inhibition markedly impaired cardiac regeneration in both zebrafish and neonatal mouse models, cementing DHA’s essential role in facilitating reparative proliferation.
One of the study’s most captivating revelations lies in the therapeutic potential of exogenous DHA supplementation. When administered to adult mice experiencing myocardial infarction, DHA induced a comprehensive remodeling of the myocardial transcriptome. This shift transitioned gene expression profiles from a phenotype dominated by injury response towards an active regenerative program. The physiological consequence was a significant enhancement in cardiac function, characterized by increased CM proliferation accompanied by a simultaneous reduction in fibrotic deposition and inflammatory infiltration.
At the mechanistic core, the research elucidates DHA’s function as a ligand for the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ or Ppard). Unlike other fatty acids such as oleic acid (OA), DHA uniquely activates Ppard, enabling it to directly engage promoter regions of key genes controlling cardiac regeneration. Notably, genes such as Mef2d, Phlda3, and Txndc5 were distinctly modulated, with Mef2d expression upregulated to promote proliferation, while Phlda3 and Txndc5 were repressed to attenuate inhibitory pathways. These gene regulatory dynamics position Ppard as a central integrator of the DHA-driven regenerative signaling cascade.
The biochemical interaction between DHA and Ppard was further solidified through advanced computational modelling techniques. Molecular docking and molecular dynamics simulations revealed that DHA binds Ppard in a conformational manner distinct from OA, providing a structural rationale for their differential activation potential. Complementing these in silico findings, mutagenesis experiments pinpointed critical amino acid residues on Ppard essential for DHA binding and transcriptional activation. These molecular insights open doors to rational drug design targeting Ppard with tailored lipid mimetics to harness cardiac regeneration.
The comprehensive nature of this study, weaving together lipidomics, genomics, computational modeling, and in vivo functional assays, underscores an evolutionarily conserved mechanism whereby DHA signaling orchestrates heart regeneration. This work not only elucidates why adult mammals lack efficient cardiac repair but also highlights a translational pathway—modulating DHA synthesis and Ppard activation—to potentially rectify this deficit. Given the prevalence of ischemic heart disease, findings from this research illuminate a promising therapeutic horizon that could mitigate progression to heart failure.
In addition to mechanistic insights, the authors provide compelling evidence that DHA’s influence extends beyond cardiomyocyte proliferation. The fatty acid also orchestrates a reduction in fibrosis and inflammation, two pathological hallmarks exacerbating post-infarction remodeling. This multifaceted effect of DHA promotes a microenvironment conducive to regeneration rather than scar formation, suggesting that therapeutic strategies augmenting DHA availability or Ppard activation might yield holistic benefits in cardiac repair.
An unexpected yet enlightening element of the study was the spatial specificity of DHA synthesis and signaling. The localized induction of synthetic enzymes and activation of Ppard in peri-infarct zones indicate that the heart’s intrinsic ability to generate localized lipid mediators is integral to initiating the regenerative cascade. This spatial precision, absent in adult mammalian hearts, signifies a crucial evolutionary divergence in cellular metabolism and gene regulation related to tissue repair.
Moreover, this research challenges the prevailing paradigm focusing predominantly on protein-based growth factors and cytokines in heart regeneration. It posits a critical lipid signaling axis as equally foundational, providing a novel molecular framework to revisit heart repair biology. The recognition of DHA and Ppard as master regulators of regeneration-related gene networks presents a paradigm shift that could inspire new classes of interventions, potentially integrating nutrition, pharmacology, and gene therapy.
From a translational perspective, the study’s findings suggest that augmenting DHA availability, either through dietary supplementation or pharmacological means, could be a viable adjunct to current therapies following myocardial infarction. This approach may trigger endogenous regenerative pathways, reducing reliance on exogenous stem cell therapies or invasive surgical interventions. Still, the precise dosing, delivery methods, and timing of DHA administration warrant rigorous clinical evaluation.
The molecular dissection of DHA’s role also paves the way for exploring Ppard-targeted agonists or antagonists with enhanced specificity. These compounds could mimic the beneficial effects of DHA without the metabolic complexities associated with fatty acid metabolism, offering more controlled therapeutic windows. Additionally, understanding how Ppard interacts with other nuclear receptors and transcription factors in the context of cardiac injury may yield insights into combinatorial regulatory networks enhancing repair.
In summary, the discovery that newly synthesized DHA accumulation is indispensable for heart regeneration marks a significant advancement in cardiovascular biology. By elucidating the DHA–Ppard axis as a key driver of cardiomyocyte proliferation and suppression of adverse remodeling, this study offers a beacon of hope for developing regenerative therapies to heal the injured heart. The evolutionary conservation of this mechanism underscores its biological importance and suggests broad applicability across species, potentially translating into human clinical benefit.
This breakthrough raises profound questions for future research: Can enhancing DHA synthesis or Ppard activation rejuvenate the adult mammalian heart’s regenerative capacity? What are the long-term effects of modulating this lipid signaling pathway? And how might this axis interact with other known mechanisms of cardiac repair? As researchers delve deeper into these inquiries, the promise of a regenerative cure for heart disease edges ever closer to reality.
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Subject of Research: Not applicable
Article Title: Accumulation of newly synthesized docosahexaenoic acid plays an essential role in heart regeneration
News Publication Date: 20-Aug-2025
Web References: http://dx.doi.org/10.1093/procel/pwaf062
Image Credits: Zimu Tang, Zhaoxiang Sun, Chun Yang, Qian Gong, Zirui Liu, Nanhui Chen, Kai Liu, Yong Wang, Ting Zhao, Shengfan Ye, Lenan Zhuang, Jiahao Lin, Wei-Qiang Tan, Jinrong Peng, Jun Chen
Keywords: Cells
