Pomegranate-Linked Compound Shows Early Promise Against Deadly Heart Failure

Nearly half of all heart failure cases belong to a form that has stumped doctors for decades. Unlike the more familiar type, where the heart pumps too weakly, this version involves a heart that squeezes normally but can’t relax properly between beats. That stiffness makes it hard for the heart to fill with blood, leaving patients breathless, fatigued, and with limited treatment options. Now, researchers say a natural compound linked to pomegranate consumption may offer a surprising new path forward.

Scientists found that a compound called urolithin A can activate a key protein in the heart through a previously unknown mechanism, helping the heart muscle relax more effectively and reducing damaging structural changes. The work was published in the journal Science Advances. In lab mice experimentally induced to develop this form of heart failure, urolithin A reversed several defining features of the disease. When researchers tested the compound in mice that lacked the specific molecular target it acts on, the same benefits were largely absent, showing that the target was essential to the compound’s effects.

Perhaps most encouraging for patients, the results also held up in engineered human heart tissue grown from stem-cell-derived heart cells. When researchers applied urolithin A to this lab-grown tissue, it contracted and relaxed more efficiently, a result that matters enormously when trying to move a discovery from animals to people.

Why This Form of Heart Failure Is So Hard to Treat

Heart failure with preserved ejection fraction, often shortened to HFpEF, accounts for close to half of all heart failure diagnoses and carries serious risks of illness and death. Most existing heart failure drugs target the heart’s pumping strength. But in HFpEF, pumping strength is not the problem. Instead, the heart muscle becomes too stiff to relax properly between beats, impairing how well it fills with blood. Patients often feel worse during physical activity, when the heart can’t keep up with increased demand.

Previous drug strategies targeting a related chemical signaling pathway had already failed in large clinical trials. Researchers suspect that’s partly because those treatments depended on a biological signal called nitric oxide, which tends to be reduced in HFpEF patients, making those drugs less effective. This new research took a different route, aiming at a protein called PKGIα, a cellular switch that helps regulate blood pressure and heart muscle relaxation, through a separate chemical mechanism that doesn’t require nitric oxide at all.

Urolithin A and the Molecular Switch at the Heart of the Discovery

At the center of this study is a single spot on the PKGIα protein: a building block called cysteine 42, abbreviated C42. When this spot is chemically modified in the right way, it activates the protein and sets off a chain of events that helps blood vessels and heart muscle loosen up between beats.

Researchers screened several natural plant-based compounds for their ability to hit this target. Urolithin A stood out immediately. Rather than activating PKGIα through the well-known mechanism shared by other compounds, urolithin A attached itself directly to C42. A lab technique that identifies the chemical makeup of molecules with high precision confirmed that urolithin A was leaving its mark directly on that spot. This distinction matters because it means the compound activates the protein in a completely different way than anything previously documented, opening a new avenue for drug design.

Once activated, PKGIα triggered a downstream effect on another protein involved in regulating calcium inside heart muscle cells. Calcium controls how heart muscle contracts and relaxes, so adjusting it has major consequences for heart function. Urolithin A pushed this calcium regulation in a direction that improved relaxation, precisely what fails in HFpEF.

Testing Urolithin A in Mice, Then in Human Heart Tissue

To test whether this mechanism could actually treat disease, researchers used a multihit mouse model designed to reproduce the human version of HFpEF as closely as possible, one involving kidney surgery, a high-fat diet, and treatment designed to produce high blood pressure. This produced an early-stage HFpEF that closely resembled what happens in human patients, including normal pumping strength alongside impaired relaxation and reduced exercise capacity.

After HFpEF was established, mice received urolithin A by mouth daily for seven days. Researchers measured heart function using ultrasound imaging. Treated mice showed meaningful improvements in several measures of heart relaxation and movement, ran farther than untreated animals, and showed reductions in heart weight, heart muscle cell size, and internal scarring in the heart tissue.

To confirm the drug was working through C42 specifically, researchers ran the same experiment in mice genetically modified so that C42 was replaced with a different building block, effectively disabling the target. In those mice, urolithin A produced little of the same benefit, showing that C42 is essential to how the compound works.

Researchers then applied urolithin A to engineered human heart tissue grown from a human stem cell line. The treatment sped up both contraction and relaxation, with contraction and relaxation times dropping substantially at 120 minutes. No dangerous irregular beating was observed.

Prior research has established that urolithin A is considered safe in humans, is absorbed well when taken orally, and stays in the bloodstream for an extended period. Studies in people have already found benefits for muscle health and general cellular maintenance. This study adds evidence of a specific and previously unknown cardiac effect to that picture, one that could potentially be useful against a condition current drugs struggle to treat.

Researchers note that the study focused exclusively on male mice, a meaningful gap given that HFpEF disproportionately affects women in the real world. Whether the same results would appear in female animals or ultimately in female patients remains an open question.

Treatment options for HFpEF remain limited, particularly when it comes to directly improving the heart’s ability to relax. This research points to something different: a well-characterized natural compound that acts through a newly discovered mechanism, with early evidence that it reaches the problem at its biological root.

Disclaimer: This article describes early-stage laboratory research conducted in mice and in engineered human heart tissue. Urolithin A has not been tested or approved as a treatment for heart failure in people, and these findings do not indicate that eating pomegranates or taking supplements can treat or prevent any heart condition. Anyone with concerns about heart health should consult a qualified medical professional.

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