In human and murine failing hearts under metabolic stress, calpain-1 activity is elevated alongside increased oxidative stress and cytosolic accumulation of HMGB1, indicating a conserved molecular pathway linking metabolic dysfunction to cardiac inflammation.

When the heart is under metabolic stress, a specific enzyme called calpain-1 becomes more active, which 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 cytoplasm. Once outside the nucleus, HMGB1 is released from the heart cells and activates immune cells, which then trigger inflammation, damage heart tissue, and weaken the heart's pumping ability.