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bioRxiv · 10.1101/2025.09.16.676684

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

Fang, S.·Huang, C.·Wu, H.·Xu, Y.·Yao, Y.·Yang, C.
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Abstract

BACKGROUNDTreating 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-rTMSs role in regulating iron homeostasis and antioxidant defense for potential therapeutic use in CIRI. METHODSA 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. RESULTSLI-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. CONCLUSIONSLI-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.

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Fang, S., Huang, C., Wu, H., Xu, Y., Yao, Y., Yang, C.. 2025-09-18. Iron Metabolism and Antioxidant Defense: The Role of LI-rTMS in Cerebral Ischemia-Reperfusion. https://doi.org/10.1101/2025.09.16.676684

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