Sodium lactate and MCT4 inhibition promote cardiomyocyte proliferation and cardiac repair via DDX17 lactylation.
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Ryan J. Tedford
Medical University of South Carolina
“In CADENCE, we observed a statistically significant reduction in pulmonary vascular resistance—an effect that was even more pronounced when adjusted for changes in hemoglobin. Importantly, this translated into improved right ventricular function, as measured by RV-PA coupling via the TAPSE-to-PASP ratio. We also saw improvements in natriuretic peptides, which correlated with gains in functional capacity—including 6-minute walk distance and New York Heart Association class—as well as prolonged time to clinical worsening in patients randomized to sotatercept. The latter are exploratory endpoints, but they are nonetheless very promising.”
Why the trial, key points, tables, limitations, PICO, abstract, media & sources
Why the trial?
Current heart failure therapies are limited by an inability to replace lost cardiomyocytes due to the negligible regenerative capacity of the adult mammalian heart. This study was conducted to elucidate the role of metabolites and metabolic reprogramming in unlocking endogenous cardiomyocyte proliferation and cardiac regeneration.
Does increasing intracellular lactate via sodium lactate administration or MCT4 inhibition promote cardiomyocyte proliferation and cardiac regeneration in postnatal and adult mice after cardiac injury?
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Key Points
To investigate whether lactate and metabolic reprogramming stimulate cardiomyocyte proliferation and enhance cardiac regeneration following heart injury.
Administered continuous sodium lactate to neonatal mice undergoing apical resection and to adult mice after myocardial infarction.
Inhibited the monocarboxylate transporter MCT4 to selectively induce intracellular lactate accumulation in cardiomyocytes.
Conducted single-nucleus RNA sequencing (snRNA-seq), quantitative lactylome, and proteomic analyses to evaluate downstream molecular mechanisms.
Sodium lactate administration stimulated cardiac regeneration after neonatal apical resection and promoted border zone cardiomyocyte proliferation, improving cardiac function following myocardial infarction in adult mice.
Selective MCT4 inhibition caused intracellular lactate accumulation, enriching alternative splicing pathways within regenerating cardiomyocyte subpopulations.
Elevated lactate induced lactylation of the RNA-binding protein DDX17, suppressing its phase separation and shifting NOTCH2 splicing toward a pro-regenerative long isoform that mediated dedifferentiation and proliferation.
Structured PICO
Does increasing intracellular lactate via sodium lactate administration or MCT4 inhibition promote cardiomyocyte proliferation and cardiac regeneration in postnatal and adult mice after cardiac injury?
PPopulation
Preclinical mouse models of neonatal apical resection and adult myocardial infarction used to evaluate lactate metabolism and cardiac regeneration.
IIntervention
Continuous administration of sodium lactate to increase myocardial lactate concentration, and specific interference/inhibition of the lactate exporter MCT4
OOutcome
Cardiac repair and regeneration, cardiomyocyte proliferation in the border zone, and cardiac function after myocardial infarctionsurrogate endpoint
Limitations
Pleiotropic systemic effects of lactate administration
Implication
Intracellular lactate accumulation via MCT4 inhibition promotes cardiomyocyte proliferation and cardiac repair in mice by inducing DDX17 lactylation, which inhibits its phase separation and alters NOTCH2 splicing.
Abstract
Background The poor prognosis and high mortality rates associated with heart failure remain critical global challenges. Current therapeutic strategies are limited by their inability to replace lost cardiomyocytes, as the regenerative capacity of the adult mammalian heart is negligible. Compelling evidence suggests that inducing a fetal-like metabolic state in cardiomyocytes can unlock endogenous regenerative potential. Consequently, elucidating the role of metabolites and metabolic reprogramming as key regulatory mechanisms in cardiac proliferation and regeneration is a pressing question in the field. Methods and Results Our preliminary data demonstrate that continuous administration of sodium lactate to increase myocardial lactate concentration in postnatal and adult mice significantly enhances cardiac repair. This treatment induced cardiac regeneration following apical resection in neonatal mice and promoted cardiomyocyte proliferation in the border zone, thereby improving cardiac function after myocardial infarction in adult mice. Recognizing the pleiotropic systemic effects of lactate, we employed a targeted screening approach based on sequencing and experimental validation. This led to the identification of a regenerative strategy centered on inhibiting the lactate exporter MCT4. Specific interference with MCT4 function caused lactate accumulation within cardiomyocytes and effectively promoted proliferation and repair. SnRNA-seq revealed significant enrichment of alternative splicing pathways in the regenerative cardiomyocyte subpopulation. Mechanistically, through integrated quantitative lactylome and proteomic analyses, we identified lactate acting as a signaling molecule. Elevated intracellular lactate promoted lactylation of DDX17, an RNA-binding protein. This post-translational modification inhibited DDX17's phase separation, consequently reducing its alternative splicing activity. This, in turn, prevented the excessive splicing of NOTCH2 into its short isoform, favoring the production of the long isoform, which promoted cardiomyocyte dedifferentiation and proliferation. Conclusion Our study identifies a novel mechanism wherein lactate, retained through MCT4 inhibition, acts as a signaling molecule to modulate alternative splicing via DDX17 lactylation-dependent phase separation. This metabolic-epigenetic crosstalk represents a critical regulatory axis for cardiac regeneration. Investigating how RNA-binding proteins (RBPs) influence alternative splicing through phase separation, as initiated by metabolic cues like lactate, opens a new avenue for understanding and enhancing heart repair. These findings provide a compelling scientific rationale for targeting lactate metabolism as a potential therapeutic strategy for the prevention and treatment of heart failure.
Cite This Study
Liu et al. (2026) studied Myocardial infarction and cardiac injury. Sodium lactate administration and MCT4 inhibition was evaluated on Cardiomyocyte proliferation, cardiac regeneration, and cardiac function. Sodium lactate administration and MCT4 inhibition promoted cardiomyocyte proliferation and cardiac repair in mice by inducing DDX17 lactylation and inhibiting its phase separation.