Ferroptosis in ischemia-reperfusion injury: molecular mechanisms and therapeutic strategies

Ferroptosis is a novel form of programmed cell death characterized by iron-dependent lipid peroxidation (LPO). It has been widely demonstrated in the last years to play a crucial pathogenic role in ischemia-reperfusion injury (IRI). The pathological basis for ferroptosis is established through disturbances in energy metabolism, iron homeostasis and mitochondrial injury during ischemic phase. During the following period of reperfusion, the surge in reactive oxygen species (ROS), along with the liberation of inflammatory mediators, and the aggravation of LPO, will further stimulate peroxidase 4 (GPX4) inactivation and augment iron load in the cells, which will greatly intensify bodily tissue injury. Ferroptosis, which operates through intricate cross-regulation with oxidative stress, immune-inflammatory responses, and autophagy, forms a multi-tiered positive feedback loop that actively contributes to injury-repair imbalance IRI pathogenesis across various organs, including the heart, brain, liver and kidney. Studies show that tissue damage and recovery can be improved by targeting system Xc^-, GPX4, ACSL4, TfR1, and NCOA4 in the body. This review summarizes the mechanisms, organ-specific manifestations, and current therapeutic strategies of ferroptosis in IRI. It is helpful for the theoretical foundation and potential direction of clinical targeted therapy.