A preclinical study found that urolithin A, a compound produced from pomegranate-related polyphenols by gut bacteria, reduced several signs of heart failure with preserved ejection fraction in mice and improved relaxation in engineered human heart tissue.
By yourNEWS Media Newsroom
A compound associated with pomegranate consumption improved heart relaxation and reduced several features of heart failure in laboratory models, according to a study published Aug. 19, 2026, in Science Advances.
Researchers found that urolithin A produced measurable benefits in mice with heart failure with preserved ejection fraction, known as HFpEF, while also improving contraction and relaxation timing in engineered human heart tissue.
The findings remain preliminary. Urolithin A has not been established or approved as a treatment for heart failure in people, and the study does not demonstrate that eating pomegranates can prevent, reverse or treat cardiovascular disease.
Instead, researchers identified a previously undescribed molecular mechanism through which the compound appears to affect the heart.
The team reported that urolithin A activates a protein known as PKGI? by binding directly to a specific site called cysteine 42, or C42. Unlike some previously studied heart-failure pathways, the mechanism does not depend on nitric oxide.
That distinction could be significant because previous attempts to treat HFpEF by targeting nitric-oxide-dependent signaling have not produced successful results in large clinical trials.
Researchers Target a Difficult Form of Heart Failure
HFpEF represents close to half of diagnosed heart failure cases, according to the study.
Unlike forms of heart failure in which the heart’s pumping ability becomes substantially weakened, patients with HFpEF can retain relatively normal squeezing function.
The central problem instead involves relaxation.
The heart muscle becomes too stiff to relax and fill adequately with blood between beats. That can limit the amount of blood available when the body requires increased circulation during exercise or other physical activity.
Patients commonly experience fatigue, shortness of breath and reduced ability to exert themselves.
Because many traditional heart failure medications were developed primarily to improve or compensate for reduced pumping function, HFpEF has remained more difficult to treat.
The researchers therefore examined whether another biological pathway could improve the heart’s ability to relax.
Their attention focused on PKGI?, a protein involved in regulating blood pressure and relaxation of heart muscle.
The study found that urolithin A interacts with that protein in a way that had not previously been described.
Urolithin A Acts on a Specific Protein Site
Urolithin A is not simply a substance contained intact in pomegranates.
It is a metabolite that can be produced when intestinal bacteria process polyphenol compounds, including punicalagin, found in pomegranates.
Previous animal research involving pomegranate-related compounds has examined possible anti-inflammatory effects, while reviews of pomegranate juice have explored its relationship to oxidative stress and cholesterol metabolism.
The new study concentrated instead on a direct cardiac mechanism.
Using mass spectrometry, researchers determined that urolithin A modified cysteine 42 on PKGI?.
That specific interaction distinguished the compound from previously documented ways of activating the protein.
Once PKGI? was activated, researchers observed downstream changes involving calcium regulation inside heart muscle cells.
Calcium movement is central to contraction and relaxation of cardiac muscle. The researchers reported that the changes associated with urolithin A allowed the heart tissue to relax more effectively.
The mechanism was also tested genetically.
When researchers used mice in which the C42 site had been disabled, most of the benefits associated with urolithin A disappeared.
That result indicated that cysteine 42 was necessary for much of the compound’s observed effect.
Seven-Day Treatment Improved Several Measures in Mice
Researchers tested urolithin A using a multihit mouse model designed to reproduce several characteristics associated with HFpEF.
The model combined kidney surgery, a high-fat diet and treatment intended to produce elevated blood pressure.
Mice then received oral urolithin A once daily for seven days.
At the end of that period, researchers reported improvements across several measurements.
Ultrasound examinations showed better measures of cardiac relaxation.
The treated mice also ran farther than untreated counterparts, suggesting an improvement in exercise capacity.
Additional analysis found lower heart weight, smaller individual heart muscle cells and reduced fibrosis.
Fibrosis involves the accumulation of scar-like tissue that can contribute to cardiac stiffness and interfere with normal heart function.
Those effects were largely lost in mice whose cysteine 42 site had been genetically disabled, strengthening the researchers’ conclusion that the PKGI?-C42 pathway plays an important role in urolithin A’s effects.
Earlier animal research has also examined urolithin A in connection with physical performance. One previous study found that aged mice receiving the compound increased running endurance by an average of 42%.
The current research, however, focused specifically on heart function and the molecular pathway involved.
Engineered Human Heart Tissue Also Responded
Researchers extended their experiments beyond mice by testing urolithin A in engineered human cardiac tissue.
The tissue was produced from a human stem cell line and allowed the investigators to examine the compound’s effects on human heart cells under controlled laboratory conditions.
After 120 minutes of exposure, the engineered tissue showed shorter contraction and relaxation times, according to the study.
Researchers did not observe irregular beating during the experiment.
The result provided evidence that the compound’s effects may not be limited exclusively to mice, although the laboratory tissue does not replicate the complexity of a living human cardiovascular system.
The researchers cautioned that substantially more work will be required before determining whether urolithin A could have therapeutic value in patients.
Study Has Significant Limitations
Several features of the research limit how broadly the findings can currently be interpreted.
Only male mice were used, despite HFpEF disproportionately affecting women.
That makes it unclear whether female animals would respond in the same way or whether sex-related biological differences could alter the compound’s effectiveness.
The engineered human heart tissue also came from only one donor stem cell line.
Researchers therefore cannot yet determine whether the findings would be consistent across people with different genetic backgrounds, ages, medical conditions or other characteristics.
Differences between mouse and human physiology create additional uncertainty.
Mouse hearts beat much faster than human hearts, and the authors cautioned that some cardiac measurements commonly used in animal research must therefore be interpreted carefully when considering possible human applications.
The seven-day treatment period was also relatively short and does not answer questions about long-term effectiveness or safety.
Findings Do Not Mean Pomegranates Treat Heart Failure
The connection between urolithin A and pomegranates could easily lead to conclusions that go beyond what the study established.
Researchers did not test whether eating pomegranates treats HFpEF.
Urolithin A production also depends partly on the composition of a person’s gut microbiome, meaning individuals may differ in their ability to generate the compound after consuming foods containing the relevant polyphenols.
The laboratory findings instead identify a specific molecular interaction that researchers believe warrants further investigation.
Clinical trials would be necessary to determine appropriate doses, safety, effectiveness and whether the compound produces meaningful benefits in people with HFpEF.
Until then, the findings remain preclinical.
Nutrition research more broadly has also emphasized whole-food dietary patterns rather than relying on isolated supplements as the primary approach for supporting cardiovascular health and blood pressure.
Research Points to a New Therapeutic Pathway
The significance of the study lies less in pomegranate consumption itself than in the newly identified pathway involving urolithin A and PKGI?.
HFpEF remains difficult to treat precisely because the heart’s primary impairment involves stiffness and inadequate relaxation rather than a simple loss of pumping strength.
By activating PKGI? through cysteine 42 without relying on nitric oxide, researchers identified a mechanism different from pathways that previously failed to produce successful treatments.
The compound improved cardiac relaxation, exercise performance, fibrosis and structural measurements in the mouse model, while engineered human heart tissue responded with faster contraction and relaxation.
The study was funded by the British Heart Foundation, the Medical Research Council of the United Kingdom and a China Scholarship Council grant.
The authors reported no competing interests.
Further animal studies and eventually carefully controlled human trials will be needed to determine whether the laboratory results can translate into a safe and effective treatment.
For now, the research provides an early indication that urolithin A may affect heart function through a previously unknown molecular target and offers scientists another potential direction for addressing a form of heart failure that remains challenging to treat.
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