Francesco Paneni remembers the moment his team saw the first clear sign: blood vessels wrapped in reprogrammed fat tissue began to relax like healthy ones again, even in samples from people with type 2 diabetes. At the University of Zurich, Paneni and his collaborators had done something radical—not by attacking cholesterol or blood sugar, but by rewriting the chemical instructions inside the thin layer of fat that hugs every artery and vein. This perivascular fat, long dismissed as inert padding, is now emerging as a central player in vascular health, especially for the 537 million people worldwide living with diabetes. When metabolism goes awry, so does this fat. It becomes inflamed, leaks harmful signals, and stiffens blood vessels—setting the stage for heart attacks and strokes. But Paneni’s team has found a way to reset it.
Working with colleagues at the University of Pisa and University Hospital Zurich, Paneni’s group targeted epigenetic 'readers'—proteins that interpret chemical tags on DNA-packaging proteins and decide which genes are switched on or off. Using BET protein inhibitors, a class of epigenetic drugs, they reprogrammed perivascular fat in both mice and human tissue samples. The result? A sweeping shift away from inflammation. The fat cells stopped flooding the vessel walls with damaging molecules, and the blood vessels themselves regained their ability to dilate properly. It was like restoring communication in a broken neighborhood.
The key to this transformation was an enzyme called hexokinase 2, a metabolic switch that, when overactive, drives fat cells to store excess lipids and emit inflammatory signals. The researchers found that silencing hexokinase 2—either by altering the epigenetic controls that regulate its gene or by targeting the enzyme directly—calmed the fat and restored vascular function. In tissue samples from diabetic patients, this approach reduced multiple markers of damage at once, something no single conventional drug can do.
The implications are profound. Current treatments for vascular risk in diabetes focus on lowering blood pressure, cholesterol, or glucose—interventions that manage symptoms after damage has begun. Epigenetic therapy, by contrast, aims to prevent that damage at its source. 'Instead of solely treating downstream risk factors such as high blood pressure, cholesterol or blood sugar after damage has already begun, epigenetic therapies aim to reprogram the tissue processes that contribute to vascular damage,' Paneni explains. While human trials are still ahead, this work opens a new frontier: not just treating disease, but reprogramming it.