In a groundbreaking study that could revolutionize the future of cardiovascular medicine, researchers have unveiled a novel therapeutic strategy to combat heart failure following myocardial infarction (MI). The team, led by Sun, Wu, Adjmi, and their colleagues, has identified that transient overexpression of the enzyme human pyruvate kinase M2 (hPKM2) in porcine cardiomyocytes mitigates the devastating progression toward heart failure in the critical aftermath of an infarct. Published in Nature Communications, this compelling discovery provides not only a deeper insight into myocardial metabolism but also a promising intervention platform that might soon transition from the bench to bedside.
Heart failure remains one of the leading causes of mortality worldwide, frequently arising as a consequence of myocardial infarction — a catastrophic event that compromises cardiac muscle viability and function. Post-MI, the heart embarks on a maladaptive remodeling journey characterized by cardiomyocyte death, fibrosis, and impaired contractility. Current treatments primarily aim to manage symptoms and prevent further cardiac damage, but effective approaches that can rescue or restore cardiomyocytes remain elusive. This study turns the spotlight on cellular metabolism, a therapeutic avenue with transformative potential, by manipulating the metabolic regulator hPKM2.
PKM2, a key glycolytic enzyme, is widely acknowledged for its dual role in energy metabolism and gene regulation. Unlike its isoform PKM1, which catalyzes pyruvate production efficiently in energy-demanding cells, PKM2 exhibits unique regulatory functions enabling cells to adapt to fluctuating metabolic demands. This enzyme is highly expressed in proliferating tissues and is now revealed to have a protective role when transiently overexpressed in myocardial cells after ischemic injury. The transient expression suggests a patient-friendly therapeutic window where metabolic modulation can be achieved without adverse effects of long-term overexpression.
The research employed a porcine model, which closely mimics human cardiac physiology and pathology, thereby enhancing the clinical relevance of their findings. Pigs subjected to experimentally induced myocardial infarction received targeted gene delivery vectors promoting hPKM2 expression specifically in cardiomyocytes. Remarkably, animals treated with this metabolic intervention demonstrated significantly improved cardiac function compared to untreated controls, as evidenced by echocardiographic and hemodynamic measurements. These improvements correlated with increased survival of cardiomyocytes and attenuated fibrotic remodeling, hallmark features of a rescued myocardium.
Mechanistically, overexpression of hPKM2 appeared to shift cardiomyocyte metabolism toward an anabolic state conducive to cell survival and repair. Enhanced glycolytic flux supplied critical intermediates to biosynthetic pathways necessary for membrane repair, antioxidant defenses, and cellular proliferation. Moreover, hPKM2’s non-metabolic functions seem to contribute to the regulation of transcription factors governing remodeling processes. This dual functionality underscores the enzyme’s complexity and its strategic advantage as a therapeutic target.
Another layer of innovation lies in the transient nature of hPKM2 overexpression. The researchers skillfully engineered a system ensuring temporary gene expression, circumventing the potential for chronic dysregulation of metabolism, which is often associated with oncogenic risks and cellular dysfunctions. This temporal control not only heightens safety but aligns with the dynamic pathophysiology of myocardial infarction, providing metabolic support during the most vulnerable phase of cardiac healing.
Delving deeper into the molecular pathways, the study identified that hPKM2 modulates several critical signaling cascades implicated in the response to ischemic stress. Enhanced activation of AMP-activated protein kinase (AMPK) and hypoxia-inducible factor 1-alpha (HIF-1α) pathways were observed, both known to promote cell survival under low oxygen conditions. This metabolic reprogramming orchestrated by hPKM2 culminates in reduced apoptosis and sustained mitochondrial function, crucial for preserving cardiomyocyte integrity.
Importantly, the study also examined the immune milieu post-MI, discovering that hPKM2 expression attenuated pro-inflammatory signaling and macrophage infiltration. Since inflammation substantially aggravates cardiac remodeling, this anti-inflammatory effect of metabolic intervention offers a double-edged therapeutic advantage. By modulating both metabolic and immune responses, hPKM2 creates a more favorable environment for heart repair and functional recovery.
The translational potential of these findings shines brightly, as the use of large animal models like pigs bridges the critical gap to human clinical trials. Future investigations will likely refine gene delivery methods, optimize timing and dosage parameters, and evaluate long-term safety to ensure therapeutic efficacy in humans. If successful, this approach could complement existing reperfusion therapies and pharmacological regimens, offering a lifeline to millions suffering from ischemic heart disease.
While gene therapy has often been impeded by delivery challenges and off-target effects, the targeted transient overexpression technique presented by Sun et al. exemplifies precision medicine at its best. The fusion of metabolic biology and cardiac therapeutics heralds a new era where enzyme modulation may be harnessed to rebuild a failing heart from within. This paradigm shift underscores the immense value of integrative research that transcends traditional boundaries.
Furthermore, the study sparks renewed interest in cardiac metabolism as a modifiable driver of disease outcomes. Historically overlooked in favor of mechanical or neurohormonal targets, metabolic interventions may soon assume center stage, empowered by molecular tools such as hPKM2 that offer specificity and safety. The potential to manipulate metabolic trajectories dynamically after injury could redefine treatment protocols and prognostic strategies.
In summary, the transient overexpression of hPKM2 in porcine cardiomyocytes demonstrates a powerful therapeutic effect that prevents heart failure post-myocardial infarction by preserving cardiomyocyte viability, reducing fibrosis, and dampening inflammation. This study is a clarion call for intensified efforts aimed at metabolic reprogramming in cardiovascular medicine. The data presented not only illuminate crucial biological processes but also chart a clear path toward clinical innovation with profound societal impact.
The implications extend beyond heart disease, inviting exploration of hPKM2 modulation in other ischemia-related conditions and disorders characterized by cellular stress and energy imbalance. As science progresses, metabolic enzymes such as hPKM2 may emerge as universal keys to unlocking regenerative healing mechanisms across diverse organ systems.
With heart disease poised to remain a dominant health threat globally, breakthroughs like this offer tangible hope. The convergence of metabolic science, gene therapy, and translational research exemplified here represents a beacon of progress, inspiring continued pursuit of novel solutions to humanity’s greatest medical challenges.
As the cardiology community eagerly anticipates clinical trial results, this study from Sun, Wu, Adjmi, and their team stands as a landmark milestone—a vivid testament to the power of metabolic engineering in rescuing the heart from the brink of failure.
Subject of Research: Myocardial infarction and heart failure prevention via metabolic enzyme modulation in cardiomyocytes.
Article Title: Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction.
Article References:
Sun, J., Wu, Y., Adjmi, M. et al. Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction. Nat Commun 16, 10354 (2025). https://doi.org/10.1038/s41467-025-65344-4
Image Credits: AI Generated
