The Crosstalk Between Ferritinophagy and Ferroptosis in Ischemic Stroke: Regulatory Mechanisms and Therapeutic Implications.

Ischemic stroke is a common cerebrovascular disease accompanied by a large number of neuronal death and severe functional impairment. In recent years, the role of ferroptosis and ferritinophagy in neuronal death after cerebral infarction has attracted great interest in the field of ischemic stroke. Ferroptosis is a newly discovered programmed cell death pattern characterized by iron overload, dysregulation of the xCT/GSH/GPX4 system, and lipid peroxidation system, which is closely associated with neurological damage after ischemic stroke. Ferritinophagy is a selective autophagy mediated by NCOA4 that regulates intracellular iron metabolism, and can be regulated by factors such as intracellular iron content and HERC2-FBXL5-IPR2 axis. Under normal physiological conditions, ferritinophagy maintains the balance of intracellular iron elements, and excessive activation can cause ferroptosis. Here, we mainly review the general mechanisms of ferroptosis and ferritinophagy, and focus on the relationship between ischemic stroke and ferroptosis/ferritinophagy. Specifically, we explored the crosstalk of ferroptosis and ferritinophagy in ischemic stroke and outlined current treatment strategies and key challenges. These observations may help to further understand the pathological events of ischemic stroke and bridge the gap between basic and translational research to provide novel insights for its treatment.