Study reveals SGLT2 inhibitors boost heart function by activating energy-producing enzyme

For years, cardiologists have watched SGLT2 inhibitors work a kind of miracle in their heart failure patients. The drugs slash hospitalizations. They reduce deaths. Yet the mechanism remained stubbornly opaque—a puzzle that gnawed at researchers because these medications were designed to work in the kidneys, not the heart. Now, a team at the University of Pennsylvania has traced the answer to a single enzyme, and the discovery may reshape how doctors think about treating one of medicine's most stubborn problems.

The research, published in Science, identifies PANK1 as the crucial target. When SGLT2 inhibitors bind to this enzyme in heart cells, they trigger a cascade: PANK1 activation boosts production of coenzyme A, a molecule that acts as the cell's energy currency. With more coenzyme A available, heart cells can convert multiple fuel sources—sugars, fats, amino acids, ketones—into usable energy far more efficiently. The result is measurable: human heart tissue from transplant recipients and donors showed improved ability to contract and relax, the two functions that fail when the heart weakens.

Zoltan Arany, the study's senior author and chair of Physiology at Penn Medicine, described the finding as a resolution to a long-standing mystery. "We identified PANK1 as a direct target of these medications and found that activating this pathway makes heart cells work better," he said. "This may explain many of the remarkable benefits patients experience with these drugs." The elegance of the discovery lies in its specificity: the researchers did not merely observe that PANK1 mattered. They showed that activating PANK1 alone reproduced many of the drug's benefits, while blocking the pathway largely eliminated them. Nicholas Forelli, an internal medicine resident in Arany's lab and co-author, noted that the evidence was "especially compelling" in these experiments, though he acknowledged that other contributing mechanisms cannot be completely ruled out.

The timing of the discovery carries its own significance. SGLT2 inhibitors often begin helping heart failure patients within days of starting treatment—a speed that has puzzled researchers for years. The PANK1 mechanism offers a plausible explanation: the drug acts directly on a fundamental energy-production pathway, not through some slow, indirect cascade. This may be why patients feel better so quickly.

Beyond explaining how the drugs work, the finding opens a new therapeutic door. SGLT2 inhibitors, while effective, carry side effects: urinary tract infections, dehydration, and in rare cases, diabetic ketoacidosis. If researchers could develop drugs that target PANK1 directly, they might capture the heart benefits while sidestepping these complications. Arany and his team are already pursuing this possibility. "One of the most exciting possibilities is developing drugs that directly target PANK1," he said. "That could allow us to capture the heart benefits while potentially avoiding some of the side effects associated with current therapies. We're actively working on that now." The work was supported by the National Institutes of Health, the Johnson Research Foundation, the Sarnoff Foundation, the Leducq Foundation, and grants from the Penn Cardiovascular Institute and the Children's Hospital of Philadelphia Frontier Program.

For now, the discovery stands as a vindication of persistence in basic science. Researchers knew SGLT2 inhibitors were doing something vital in the heart. They simply had not thought to look at PANK1. "Honestly, no one thought to look," Arany reflected. The enzyme had been hiding in plain sight, waiting for someone to ask the right question. Now that the answer is known, the next phase of drug development can begin.