FERROPTOSIS IN EARLY BRAIN INJURY AFTER SUBARACHNOID HEMORRHAGE: PATHOPHYSIOLOGICAL MECHANISMS OF IRON HOMEOSTASIS, FERRITINOPHAGY, AND LIPID PEROXIDATION

Abstract

Subarachnoid hemorrhage (SAH) is a severe cerebrovascular condition in which 
early brain injury (EBI), particularly during the first 72 hours, contributes substantially 
to neurological deterioration and poor outcome. Ferroptosis has emerged as a potential 
mechanism linking post-hemorrhagic iron accumulation to oxidative membrane 
damage. This narrative review examines the relationship between disturbed iron 
homeostasis, ferritinophagy, lipid peroxidation, and impaired antioxidant defense 
during EBI after SAH. Hemoglobin and heme degradation increase the availability of 
redox-active iron, thereby expanding the labile iron pool and facilitating reactive 
oxygen species generation. Alterations in transferrin receptor 1, divalent metal 
transporter 1, ferroportin, and hepcidin signaling may further disrupt intracellular iron 
balance. In parallel, NCOA4-dependent ferritinophagy can mobilize ferritin-bound 
iron and potentially amplify the labile iron pool. The glutathione-dependent GPX4 
pathway normally limits phospholipid hydroperoxide accumulation; its impairment 
therefore increases the susceptibility of PUFA-rich neuronal membranes to oxidative 
injury.