Thioredoxin system dysregulation and calpain activation drive myocardial disulfidptosis via pathological disulfide bonds remodeling.

Abstract

Myocardial infarction (MI) remains a leading cause of death and disability worldwide, yet the molecular mechanisms underlying cardiomyocyte death during ischemic injury are not fully understood. Here, we identify disulfidptosis-a recently described form of regulated cell death-as a novel contributor to myocardial ischemic injury. In ischemia-mimetic models, glucose and oxygen deprivation lead to NADPH depletion and excessive disulfide bond accumulation in cardiomyocytes, accompanied by F-actin cytoskeletal collapse, a defining feature of disulfidptosis. Mechanistically, impairment of the NADPH/thioredoxin (Trx) system amplifies disulfide stress, while calcium overload-induced activation of calpains disrupts cytoskeletal protein conformation, removing steric constraints that normally prevent aberrant disulfide bonding. The synergistic effect of these two processes creates favorable oxidative and spatial structural conditions for the occurrence of disulfidptosis. Inhibition of Trx activity promotes disulfide death; pharmacological inhibition of calpainthe or blockade of calcium overload significantly reduces disulfide accumulation and preserves cytoskeletal integrity, confirming their crucial role in ischemia-induced disulfidptosis. Based on the above findings, this study confirms that disulfidptosis represents a previously unrecognized mechanism of cardiomyocyte death in myocardial ischemia, revealing the mechanistic link between metabolic stress, redox imbalance, and cytoskeletal collapse; and proposing a novel pathological remodeling process of disulfide bonds characterized by "Cleavage-Fragmentation-Mismatch". These insights provide new conceptual and therapeutic perspectives for cardioprotection.