Pharmacological inhibition of calpain-1 with calpeptin in mice fed an ultra-processed diet reduces myocardial oxidative stress, lowers HMGB1 levels, decreases macrophage-driven inflammation, and improves cardiac function without altering systemic metabolic parameters.

When the heart is exposed to unhealthy fats from an ultra-processed diet, a protein called calpain-1 becomes overactive and causes mitochondria in heart cells to leak harmful molecules called reactive oxygen species. These molecules chemically alter another protein, HMGB1, forcing it to leave the nucleus and escape into the space around the heart cells. Once outside, HMGB1 activates immune cells called macrophages, making them release inflammatory signals that damage heart tissue, stiffen the heart muscle, and weaken its pumping ability.