Authors
Chao Yu, Yan Song, Manhui Zhu, Jiabing Shen, Yuting Zhang, Yufei Wang, Yuhang Na
Published in
Free radical biology & medicine. Nov 12, 2026. Epub Nov 12, 2026.
Abstract
Ferroptosis has emerged as an important component of secondary injury after traumatic brain injury (TBI), yet the in vivo contribution of neuronal glutathione peroxidase 4 (GPX4), the core lipid hydroperoxide detoxifying enzyme, remains incompletely defined. Here we used 10-12-week-old male Gpx4fl/fl;CamKII-Cre mice to test whether postnatal neuronal GPX4 deficiency increases vulnerability to TBI and whether the ferroptosis inhibitor ferrostatin-1 (Fer-1) provides mechanistic rescue. Because CamKII-Cre-mediated recombination begins during early postnatal development, this model reflects postnatal neuronal GPX4 deficiency and cannot isolate an acute, adult-only loss; accordingly, mechanistic conclusions are grounded in the consistency of biochemical, histological, ultrastructural and pharmacological rescue data rather than in temporal isolation of an adult-onset deletion effect. Controlled cortical impact caused an acute decline in neuronal GPX4, maximal at 24 h, with relative preservation in astrocytes and microglia. Compared with littermate controls, GPX4-nKO mice developed worse neurological deficits, greater brain edema, higher Evans blue extravasation and intracranial pressure, amplified lipid peroxidation, reduced glutathione, increased ACSL4, decreased SLC7A11, more ferroptotic mitochondrial injury, larger lesion volume, enhanced neuroinflammation and poorer long-term behavioral recovery. Fer-1 administered at 1 h and 6 h post-injury lowered malondialdehyde and 4-hydroxynonenal, restored glutathione, reduced dying neuron density and lesion volume, and improved acute and chronic outcomes in GPX4-nKO mice. Together, these data support a mechanistic model in which postnatal neuronal GPX4 deficiency sensitizes the injured brain to ferroptotic secondary damage, while Fer-1 rescue strengthens the conclusion that lipid peroxidation-driven ferroptosis is a major effector pathway downstream of neuronal GPX4 loss after TBI. Ferroptosis involvement is supported by converging evidence, although parallel contributions from other injury mechanisms cannot be fully excluded in this in vivo context.
PMID:
43020442
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.
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