Urolithin A reverses stiff-heart failure in mice study

If you have ever been told your heart "relaxes stiffly" between beats, or a relative has been diagnosed with heart failure despite a normal pumping (ejection) fraction, you have run into one of cardiology's most stubborn problems. Heart failure with preserved ejection fraction (HFpEF) is common, hard to treat, and every major drug tried against it in the clinic has come up short. A new study points to an unlikely candidate: a molecule your own gut bacteria make when you eat pomegranates, walnuts, and certain berries.

Key takeaways

• Researchers found that urolithin A, a compound gut bacteria produce from polyphenols in pomegranates and other foods, reversed heart stiffening and remodeling in a mouse model of HFpEF.
• The compound worked by directly modifying a single protein switch (cysteine 42, on an enzyme called PKGIα) that controls how well the heart relaxes between beats.
• It also improved relaxation and contraction speed in lab-grown human heart tissue, which is an early sign the mechanism may translate to people.
• This is preclinical work, done in male mice and donor-derived human tissue in a dish, not a human clinical trial, and it does not mean eating more pomegranates will treat heart failure.

Urolithin A Targets a Cysteine Switch That Controls Heart Relaxation

Researchers at King's College London found that urolithin A, a metabolite (a breakdown product) that gut bacteria generate from polyphenols in pomegranates, walnuts, and berries, directly chemically modifies a single amino acid, cysteine 42, on a heart enzyme called PKGIα (protein kinase G, a signaling enzyme that helps blood vessels and heart muscle relax). That modification switches the enzyme on through a route separate from the one nearly every existing heart-failure drug relies on, according to the study, published in Science Advances. In the same enzyme-screening experiments, two related plant compounds, quercetin and fisetin (both flavonoids, a class of plant polyphenols found in onions, apples, and berries), activated PKGIα through a more conventional route, but only urolithin A produced the noncanonical activation pattern the team then chased into animal and human-tissue experiments.

Heart Failure With a Normal Pump Is the Type Doctors Struggle Most to Treat

HFpEF accounts for nearly half of all heart failure diagnoses and disproportionately affects older adults, women, and people with obesity, diabetes, or high blood pressure. Unlike the more familiar form of heart failure where the heart's main pumping chamber weakens, in HFpEF the heart squeezes normally but does not relax and fill properly between beats, leaving patients short of breath and exercise-intolerant. That distinction matters clinically: drugs that helped the weak-pump form of heart failure, including the PDE5 inhibitor sildenafil and the sGC stimulator vericiguat, have repeatedly failed to move the needle in HFpEF trials, leaving few disease-modifying options. The new findings target a mechanism distinct from those failed drug classes, which is part of why the researchers see it as promising.

A Multihit Mouse Model and Lab-Grown Human Heart Tissue Built the Case

The researchers used what they describe as a multihit mouse model designed to mimic human HFpEF more closely than older single-stressor models: male mice underwent removal of one kidney, were given a salt-retaining hormone (DOCA), and were switched to a high-fat diet, combining the metabolic and hypertensive stress seen in many real-world HFpEF patients. After three weeks, once cardiac dysfunction was established, mice received either urolithin A or a placebo by mouth for seven days. To confirm the cysteine-42 mechanism specifically, the team ran the same experiment in genetically engineered mice carrying a mutated version of PKGIα that cannot be activated at that site, and the benefit largely disappeared in those animals. Separately, the researchers tested urolithin A on engineered heart tissue (EHT), a lab-grown three-dimensional patch of beating heart muscle made from human stem cells, to see whether the mechanism held up in human cells rather than mouse ones.

What Improved, in the Mice and in the Human Tissue

In the treated wild-type mice, seven days of oral urolithin A improved several measures of diastolic function, the heart's relaxation and filling phase that is specifically impaired in HFpEF, including global longitudinal strain and the E/e' ratio (an ultrasound-based measure doctors use to estimate filling pressure). Heart weight and left ventricular mass dropped, scar tissue (fibrosis) in the heart muscle decreased, and the mice ran farther on voluntary running wheels, an exercise-capacity proxy. In the human engineered heart tissue, a 100 micromolar dose of urolithin A sped up both relaxation and contraction without weakening the tissue's peak contractile force or triggering arrhythmias, with relaxation time at 50% recovery cut by 36% after two hours of exposure. Because the same cysteine-42 mechanism was confirmed in both the mouse hearts and the human tissue, the researchers argue it is a plausible drug target rather than a mouse-specific quirk, though that argument still rests on preclinical evidence.

Eating Pomegranates Is Not the Same as Taking the Dose Used Here

It is worth being precise about what this study does and does not show. Urolithin A is not absorbed directly from pomegranates, walnuts, or berries; it is produced when gut bacteria break down plant compounds called ellagitannins found in those foods, and how much any individual makes depends heavily on which gut microbes they carry. The mice in this study received a specific oral dose (50 milligrams per kilogram of body weight daily) of purified urolithin A, not pomegranate juice or extract, so the results say nothing about whether eating more pomegranates would raise urolithin A high enough, or consistently enough, to matter for a human heart. If you have been told you have HFpEF or diastolic dysfunction, this study is not grounds to start a supplement on your own. It is, at most, a reason to ask a cardiologist whether any trials of urolithin A-based therapies are underway and worth watching, rather than to change your diet or supplement routine based on a mouse study.

The Biggest Open Question Is Whether This Holds Up in Women and in People

The study has real limits the researchers themselves flag. It used only male mice, even though human HFpEF disproportionately affects women, and the authors explicitly note that whether the same benefit appears in female animals remains untested. It also comes from a single laboratory using one mouse model and heart tissue derived from a single human donor's stem cell line, so independent replication in other labs and other tissue donors has not yet happened. Most importantly, urolithin A has been given to people before in unrelated trials, at doses ranging from 250 to 2,000 milligrams, and shown to be well tolerated, safe, and beneficial for muscle and mitochondrial health markers in a randomized trial in middle-aged and older adults and in an earlier dose-finding safety study, but none of that prior human safety data comes from people with heart failure, and no clinical trial has yet tested it as a heart-failure treatment.

Researchers See a New Drug Target, Not a Finished Drug

The authors frame cysteine 42 on PKGIα as a previously unrecognized therapeutic target for HFpEF, and argue urolithin A's known human safety profile from other applications makes it a reasonable starting point for that class of drug rather than the end product itself. The stated next step, echoed by the researchers' own framing of the findings, is testing whether directly and more potently activating this cysteine switch, either with urolithin A itself or with new compounds purpose-built for the site, improves outcomes in a human HFpEF trial. No timeline for such a trial has been announced, and getting from a validated mouse and tissue mechanism to an approved therapy typically takes years and can fail at any stage, as the string of previous HFpEF drug disappointments shows.

Common Questions

Is urolithin A a supplement I can buy? Yes, urolithin A supplements exist commercially for general mitochondrial and muscle health, largely based on prior aging-focused trials. This particular study did not test a commercial supplement for heart failure, and no dose or formulation for that use has been established or approved.

Does this mean pomegranates are good for heart failure? Not based on this study. The mice received a purified, controlled oral dose of urolithin A, not pomegranate juice or fruit, and how much urolithin A any person's gut bacteria produce from food varies widely between individuals.

What is HFpEF, in plain terms? It is a form of heart failure where the heart's main pumping chamber contracts normally but does not relax and fill with blood properly between beats, causing breathlessness and reduced exercise capacity, especially in older adults.

When might this reach human patients? There is no announced timeline. The findings identify a new biological target and show it works in mice and in human heart tissue grown in a lab, but a human clinical trial for HFpEF specifically has not yet been conducted.

References

1. Jie Su, Yue Zhao, Pierre Coleman, et al. (2026). Targeting PKGIα Cys ⁴² attenuates cardiac dysfunction in heart failure with preserved ejection fraction. Science Advances. https://doi.org/10.1126/sciadv.aec8088
2. Anurag Singh, Davide D’Amico, Pénélope A. Andreux, et al. (2022). Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2022.100633
3. Pénélope A. Andreux, William Blanco-Bose, Dongryeol Ryu, et al. (2019). The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nature Metabolism. https://doi.org/10.1038/s42255-019-0073-4