Lab study links heart-failure drugs to energy enzyme PANK1

In a Penn Medicine laboratory, human heart cells were given a closer look at a drug class patients already know: SGLT2 inhibitors. Researchers found that the medicines directly activate PANK1, an enzyme that helps heart cells produce and use energy, and that this activation improved the cells’ ability to contract and relax.

The mechanism fills in a gap that has persisted since these drugs moved from diabetes care into heart failure treatment. Their original target, the SGLT2 protein, is found in the kidneys, while the clinical benefits appear in the heart. Using human heart tissue from transplant recipients and donors, the team found that SGLT2 inhibitors increased the heart’s ability to use sugars, fats, amino acids and ketones as fuel.

PANK1 controls the first and most important step in producing coenzyme A, or CoA, a molecule central to converting nutrients into energy. The researchers found that the drugs physically bind to PANK1 and activate it. Activating PANK1 alone reproduced many of the drugs’ benefits; blocking the pathway largely removed them. The researchers say other mechanisms cannot be completely ruled out, but the evidence points to PANK1 as a major driver.

And so what, concretely? The finding may help explain why SGLT2 inhibitors can begin benefiting heart-failure patients within days. It also gives drug developers a more specific target: medicines that activate PANK1 directly could potentially retain heart benefits while avoiding some side effects associated with current treatments, including urinary tract infections, dehydration and rare diabetic ketoacidosis.

That possibility is still ahead. The results come from human cells and tissue in laboratory experiments, not from a clinical test of a PANK1 drug. The study, led by Zoltan Arany’s team at the University of Pennsylvania and published in Science, identifies a biological route; it does not yet establish a new medicine or prove that PANK1 explains every benefit of SGLT2 inhibitors.