Cardiac-specific inhibition of calpain-1 in mice fed an ultra-processed diet reduces oxidative stress, decreases cytosolic accumulation of HMGB1, attenuates myocardial inflammation, and improves both diastolic and systolic heart function, independent of systemic metabolic changes.

When the heart is exposed to unhealthy fats from an ultra-processed diet, a specific enzyme called calpain-1 becomes overactive and causes mitochondria in heart cells to leak harmful molecules called reactive oxygen species. These molecules chemically alter a protein called HMGB1, forcing it to move out of the cell's nucleus and into the surrounding fluid. Once outside the nucleus, HMGB1 escapes the heart cell and signals nearby immune cells to become inflammatory, which damages heart tissue, stiffens the heart muscle, and weakens its ability to pump and relax properly.