Phase-dependent iron dysmetabolism in myocardial ischemia-reperfusion injury: From mechanisms to therapies.

Myocardial ischemia-reperfusion injury (MIRI) remains a critical clinical challenge, often worsening myocardial damage after reperfusion therapy for acute myocardial infarction (AMI). Phase-dependent dysregulation of iron homeostasis is critically involved in the pathogenesis of MIRI. Ischemia leads to depletion of the labile iron pool (LIP) and iron accumulation in cardiomyocytes, whereas reperfusion leads to iron overload and oxidative stress. These changes destroy cellular homeostasis, triggering ferroptosis and other programmed cell death pathways. Potential therapeutic targets have been identified through molecular mechanisms regulating ferritinophagy, hepcidin modulation, and transferrin receptor 1-mediated iron transport. This review summarizes research progress in these phase-specific changes in iron metabolism during myocardial ischemia and reperfusion, emphasizing their roles in oxidative stress and cell damage. Potential therapeutic strategies integrate the correction of dysregulated homeostasis into clinical trials using drugs that target AMI and MIRI, offering perspectives for the development of novel treatments.