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Peer-reviewedCC BY-NC-NDRedox Biology

Itaconate protects the blood-brain barrier by preserving microvascular bioenergetics after traumatic brain injury

  • Ning Liu
  • Di Zhou1
  • Mengxuan Shi1
  • Yuwen Xiu1
  • Yinghua Jiang1
  • Yingjie Wang1
  • Gaby A. Moyano1
  • Jack L. McGuire2
  • Amin Iskender2
  • Mitchell D. Kilgore2
  • Lixiang Chen1
  • Charles Vidoudez3
6 more authors
  • Yadan Li4
  • Thin Yadanar Sein2
  • Jia Fan5
  • Prasad V.G. Katakam6
  • Aaron S. Dumont1
  • Xiaoying Wang
6 affiliations
  1. 1Clinical Neuroscience Research Center, Department of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Department of Neurosurgery, School of Medicine, University of Virginia, Charlottesville, VA, 22903, USA
  2. 2Clinical Neuroscience Research Center, Department of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
  3. 3Harvard Center for Mass Spectrometry, Harvard University, Cambridge, MA, 02138, USA
  4. 4Tulane University Translational Sciences Institute, New Orleans, LA, 70112, USA
  5. 5Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, LA, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
  6. 6Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
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Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability, yet effective pharmacological therapies remain unavailable. Early blood–brain barrier (BBB) disruption accelerates neuroinflammation and secondary brain injury. It has been well recognized that brain microvascular endothelial cells (BMECs) depend on mitochondrial oxidative metabolism to maintain BBB integrity. Here, we investigated the role of the mitochondria-derived immunometabolite itaconate in regulating cerebrovascular bioenergetics and BBB integrity after TBI. Using a controlled cortical impact model, we found that TBI induced early Irg1 upregulation but paradoxically reduced fatty acid–derived itaconate levels in brain microvessels (MVs). TBI also created a hypoxic microenvironment that disrupted the Irg1/itaconate axis in BMECs. Genetic Irg1 deficiency exacerbated microvascular metabolic dysfunction, particularly deficits in fatty acid oxidation (FAO), and BBB breakdown, whereas treatment with 4-octyl itaconate (4-OI) restored mitochondrial metabolism/bioenergetics in brain MVs within 12 h after injury and preserved BBB integrity. Mechanistically, TBI and hypoxia suppressed carnitine palmitoyltransferase 1A (CPT1a), whereas 4-OI restored CPT1a expression, enhanced FAO, and activated Nrf2 signaling, thereby preserving tight junction proteins and VE-cadherin in hypoxia-exposed human BMECs. Together, these findings identify itaconate as a critical regulator of endothelial mitochondrial metabolism and BBB integrity following TBI and support therapeutic targeting of the Irg1/itaconate pathway to prevent secondary neurovascular injury.

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Cite

BibTeXRIS
BibTeX
@article{liu2026itaconate,
  title = {{Itaconate protects the blood-brain barrier by preserving microvascular bioenergetics after traumatic brain injury}},
  author = {Ning Liu and Di Zhou and Mengxuan Shi and Yuwen Xiu and Yinghua Jiang and Yingjie Wang and Gaby A. Moyano and Jack L. McGuire and Amin Iskender and Mitchell D. Kilgore and Lixiang Chen and Charles Vidoudez and Yadan Li and Thin Yadanar Sein and Jia Fan and Prasad V.G. Katakam and Aaron S. Dumont and Xiaoying Wang},
  journal = {Redox Biology},
  year = {2026},
  month = oct,
  doi = {10.1016/j.redox.2026.104446},
  url = {https://doi.org/10.1016/j.redox.2026.104446},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Itaconate protects the blood-brain barrier by preserving microvascular bioenergetics after traumatic brain injury
AU  - Ning Liu
AU  - Di Zhou
AU  - Mengxuan Shi
AU  - Yuwen Xiu
AU  - Yinghua Jiang
AU  - Yingjie Wang
AU  - Gaby A. Moyano
AU  - Jack L. McGuire
AU  - Amin Iskender
AU  - Mitchell D. Kilgore
AU  - Lixiang Chen
AU  - Charles Vidoudez
AU  - Yadan Li
AU  - Thin Yadanar Sein
AU  - Jia Fan
AU  - Prasad V.G. Katakam
AU  - Aaron S. Dumont
AU  - Xiaoying Wang
PY  - 2026
DA  - 2026/10/20
JO  - Redox Biology
DO  - 10.1016/j.redox.2026.104446
UR  - https://doi.org/10.1016/j.redox.2026.104446
AB  - Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability, yet effective pharmacological therapies remain unavailable. Early blood–brain barrier (BBB) disruption accelerates neuroinflammation and secondary brain injury. It has been well recognized that brain microvascular endothelial cells (BMECs) depend on mitochondrial oxidative metabolism to maintain BBB integrity. Here, we investigated the role of the mitochondria-derived immunometabolite itaconate in regulating cerebrovascular bioenergetics and BBB integrity after TBI. Using a controlled cortical impact model, we found that TBI induced early Irg1 upregulation but paradoxically reduced fatty acid–derived itaconate levels in brain microvessels (MVs). TBI also created a hypoxic microenvironment that disrupted the Irg1/itaconate axis in BMECs. Genetic Irg1 deficiency exacerbated microvascular metabolic dysfunction, particularly deficits in fatty acid oxidation (FAO), and BBB breakdown, whereas treatment with 4-octyl itaconate (4-OI) restored mitochondrial metabolism/bioenergetics in brain MVs within 12 h after injury and preserved BBB integrity. Mechanistically, TBI and hypoxia suppressed carnitine palmitoyltransferase 1A (CPT1a), whereas 4-OI restored CPT1a expression, enhanced FAO, and activated Nrf2 signaling, thereby preserving tight junction proteins and VE-cadherin in hypoxia-exposed human BMECs. Together, these findings identify itaconate as a critical regulator of endothelial mitochondrial metabolism and BBB integrity following TBI and support therapeutic targeting of the Irg1/itaconate pathway to prevent secondary neurovascular injury.
SN  - 2213-2317
ER  -