ER stress sensor PERK drives ferroptosis by disrupting MAMs-mediated mitochondrial homeostasis and promoting mtROS accumulation in acute myocardial infarction

Acute myocardial infarction (AMI) is a life-threatening condition in which ferroptosis represents an important form of regulated cardiomyocyte death, yet its upstream regulatory mechanisms remain incompletely understood. In this study, we investigated the role of the endoplasmic reticulum (ER) stress sensor PERK in the control of ferroptosis during ischemic injury. Using cardiac-specific PERK knockout mice, oxygen-glucose-deprived cardiomyocytes, and myocardial tissues from patients with AMI, we examined cardiac injury responses, mitochondrial function, ferroptosis-related protein expression, and the interaction between PERK and the mitochondrial fusion protein MFN2. We found that PERK expression and activation were markedly elevated in both murine and human AMI hearts. PERK activation disrupted mitochondria-ER contacts (MAMs), caused mitochondrial depolarization and excessive oxidative stress, and suppressed key antioxidant proteins, including xCT, GPX4, and FTH1, thereby promoting ferroptotic cell death. Conversely, genetic deletion or pharmacological inhibition of PERK preserved mitochondrial integrity, restored redox homeostasis, reduced infarct size, and improved cardiac function. Mechanistically, PERK interacted with MFN2 to modulate MAM stability, and transcriptomic analysis together with human validation supported a central role for the PERK-MAM-mtROS axis in ischemic injury. These findings demonstrate that PERK drives cardiomyocyte ferroptosis by destabilizing MAMs and enhancing mitochondrial oxidative stress, and they identify PERK as a promising therapeutic target for AMI.