Iron Metabolism and Antioxidant Defense: The Role of LI-rTMS in Cerebral Ischemia-Reperfusion

BACKGROUND: Treating cerebral ischemia/reperfusion injury (CIRI) is challenging, with iron metabolism imbalances and oxidative stress worsening the condition. While low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) shows potential in brain protection, its effects on iron processing and antioxidant use are unclear. This study explored LI-rTMS's role in regulating iron homeostasis and antioxidant defense for potential therapeutic use in CIRI. METHODS: A rat model of CIRI was established using a filament insertion technique, followed by neurological and infarct volume assessments. In PC12 cells, oxidative damage was induced with H2O2 or ferric ammonium citrate (FAC), then treated with LI-rTMS or deferoxamine (DFP). Parameters measured included oxidative stress markers, iron metabolism markers, and mitochondrial integrity. Gene knockdown and overexpression experiments explored mechanisms involving LI-rTMS and ACSL4. RESULTS: LI-rTMS improved neurological deficits by boosting GPX4 activity and inhibiting the ACSL4-LPCAT3-LOX axis, reducing lipid peroxidation. It restored iron balance by lowering TFR and DMT1, decreasing ferritin and hepcidin, and increasing FPN for better iron efflux. LI-rTMS also prevented the Fenton reaction, reduced ROS production, and maintained mitochondrial structure and transmembrane potential. CONCLUSIONS: LI-rTMS offers neuroprotection by regulating iron homeostasis through dual pathways: boosting export (via FPN) and reducing uptake/storage (via TFR/DMT1/FE). It also provides ACSL4-dependent antioxidant benefits, suggesting its potential to prevent ferroptosis in CIRI.