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<p>Traumatic brain injury (TBI) contributes to neurological disability, in part through neuronal ferroptosis. Although orexin-A (OXA) attenuates TBI-induced ferroptosis and functional impairment, the underlying mechanism remains unclear. We investigated whether OXA exerts neuroprotection via the orexin receptor 1 (OX1R)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway through in vitro and in vivo experiments. Rat TBI models were induced by modified Feeney’s method alongside Erastin-treated PC12 ferroptosis models. OX1R (intracerebroventricular) and Nrf2 (intraperitoneal) inhibitors defined pathway involvement. Neurological function was assessed through modified neurological severity scores (mNSS) and inverted screen test (IST). Pathological and molecular evaluations included Evans blue staining, hematoxylin–eosin staining, Fluoro-Jade B staining, CCK-8 assay, cell migration assays, transmission electron microscopy, biochemical assays, Western blot, quantitative polymerase chain reaction, and immunofluorescence. In the TBI rat model, OXA administration significantly reduced mNSS scores, prolonged grip latency in the IST, and attenuated blood-brain barrier disruption and neuronal damage. OXA suppressed oxidative stress, upregulated OX1R and HO-1 protein expression, elevated ferroptosis-related markers (SLC7A11 and GPX4), and promoted the nuclear translocation of Nrf2. In vitro, OXA counteracted Erastin-induced cytotoxicity in PC12 cells, ameliorated mitochondrial damage, and restored SLC7A11 and GPX4 levels. Notably, OXA’s neuroprotective effects were substantially diminished upon OX1R or Nrf2 blockade. In conclusion,&#xa0;OXA mitigates neurological deficits, preserves blood-brain barrier integrity, reduces oxidative stress, and inhibits neuronal ferroptosis following TBI, mechanistically linked to activation of the OX1R/Nrf2 signaling pathway. These findings provide a novel therapeutic rationale for targeting ferroptosis in TBI management.</p>

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Orexin-A Mitigates Traumatic Brain Injury by Inhibiting Neuronal Ferroptosis Through Orexin Receptor 1/Nuclear Factor Erythroid 2-Related Factor 2 Signaling Pathway

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Junwei Kang,
  • Binkai Ren,
  • Jia Wang,
  • Yunliang Tang,
  • Xiaoyang Dong

摘要

Traumatic brain injury (TBI) contributes to neurological disability, in part through neuronal ferroptosis. Although orexin-A (OXA) attenuates TBI-induced ferroptosis and functional impairment, the underlying mechanism remains unclear. We investigated whether OXA exerts neuroprotection via the orexin receptor 1 (OX1R)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway through in vitro and in vivo experiments. Rat TBI models were induced by modified Feeney’s method alongside Erastin-treated PC12 ferroptosis models. OX1R (intracerebroventricular) and Nrf2 (intraperitoneal) inhibitors defined pathway involvement. Neurological function was assessed through modified neurological severity scores (mNSS) and inverted screen test (IST). Pathological and molecular evaluations included Evans blue staining, hematoxylin–eosin staining, Fluoro-Jade B staining, CCK-8 assay, cell migration assays, transmission electron microscopy, biochemical assays, Western blot, quantitative polymerase chain reaction, and immunofluorescence. In the TBI rat model, OXA administration significantly reduced mNSS scores, prolonged grip latency in the IST, and attenuated blood-brain barrier disruption and neuronal damage. OXA suppressed oxidative stress, upregulated OX1R and HO-1 protein expression, elevated ferroptosis-related markers (SLC7A11 and GPX4), and promoted the nuclear translocation of Nrf2. In vitro, OXA counteracted Erastin-induced cytotoxicity in PC12 cells, ameliorated mitochondrial damage, and restored SLC7A11 and GPX4 levels. Notably, OXA’s neuroprotective effects were substantially diminished upon OX1R or Nrf2 blockade. In conclusion, OXA mitigates neurological deficits, preserves blood-brain barrier integrity, reduces oxidative stress, and inhibits neuronal ferroptosis following TBI, mechanistically linked to activation of the OX1R/Nrf2 signaling pathway. These findings provide a novel therapeutic rationale for targeting ferroptosis in TBI management.