Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association · 2026
Deferoxamine attenuates early brain injury after subarachnoid hemorrhage by inhibiting ferroptosis and preserving mitochondrial function and oxidative phosphorylation via Nrf2 signaling.
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Liu Guodong, Shan Wen, Zhang Zhiyuan, Wei Wuting, Wei Yu, Bai Wanshan, Dai Jing, Lin Yixing
Аннотация
BACKGROUND: Early brain injury (EBI) occurring within the first 72 h is a critical determinant of outcome after subarachnoid hemorrhage (SAH), yet effective treatments remain limited. Ferroptosis and mitochondrial dysfunction are central mechanisms in EBI. This study investigated whether deferoxamine (DFO), a clinically approved iron chelator, alleviates EBI after SAH via ferroptosis inhibition and mitochondrial restoration.
METHODS: A rat SAH model was established by endovascular perforation. Neurological scores, blood-brain barrier integrity, and brain edema were assessed. TUNEL staining evaluated cortical cell death. Biochemical assays measured malondialdehyde and ATP levels. Western blotting and qPCR assessed ferroptosis-related proteins, mitochondrial dynamics, respiratory chain complexes, and Nrf2/PGC1α signaling. Transmission electron microscopy examined mitochondrial ultrastructure.
RESULTS: DFO significantly improved neurological function, reduced blood-brain barrier leakage, and alleviated brain edema after SAH. TUNEL staining revealed reduced cortical cell death with DFO treatment. DFO restored GPX4 and xCT expression, suppressed malondialdehyde accumulation, and normalized iron homeostasis proteins (Fpn, TfR1, IREB2), indicating inhibition of ferroptosis. Transmission electron microscopy demonstrated that DFO prevented SAH-induced mitochondrial swelling and fragmentation, consistent with increased Mfn2 and decreased Fis1 expression. Furthermore, DFO elevated ATP levels and upregulated respiratory chain complexes I-V. Mechanistically, DFO activated Nrf2/PGC1α/Tfam signaling, linking ferroptosis suppression with enhanced mitochondrial biogenesis and energy metabolism.
CONCLUSIONS: DFO mitigates EBI after SAH by concurrently inhibiting ferroptosis and preserving mitochondrial oxidative phosphorylation, partly via activation of the Nrf2 pathway. These findings suggest DFO as a promising therapeutic strategy because it concurrently targets the interconnected mechanisms of ferroptosis and mitochondrial dysfunction, rather than acting solely as a lipid peroxidation inhibitor.
METHODS: A rat SAH model was established by endovascular perforation. Neurological scores, blood-brain barrier integrity, and brain edema were assessed. TUNEL staining evaluated cortical cell death. Biochemical assays measured malondialdehyde and ATP levels. Western blotting and qPCR assessed ferroptosis-related proteins, mitochondrial dynamics, respiratory chain complexes, and Nrf2/PGC1α signaling. Transmission electron microscopy examined mitochondrial ultrastructure.
RESULTS: DFO significantly improved neurological function, reduced blood-brain barrier leakage, and alleviated brain edema after SAH. TUNEL staining revealed reduced cortical cell death with DFO treatment. DFO restored GPX4 and xCT expression, suppressed malondialdehyde accumulation, and normalized iron homeostasis proteins (Fpn, TfR1, IREB2), indicating inhibition of ferroptosis. Transmission electron microscopy demonstrated that DFO prevented SAH-induced mitochondrial swelling and fragmentation, consistent with increased Mfn2 and decreased Fis1 expression. Furthermore, DFO elevated ATP levels and upregulated respiratory chain complexes I-V. Mechanistically, DFO activated Nrf2/PGC1α/Tfam signaling, linking ferroptosis suppression with enhanced mitochondrial biogenesis and energy metabolism.
CONCLUSIONS: DFO mitigates EBI after SAH by concurrently inhibiting ferroptosis and preserving mitochondrial oxidative phosphorylation, partly via activation of the Nrf2 pathway. These findings suggest DFO as a promising therapeutic strategy because it concurrently targets the interconnected mechanisms of ferroptosis and mitochondrial dysfunction, rather than acting solely as a lipid peroxidation inhibitor.