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4-Octyl itaconate attenuates cerebral ischemia reperfusion injury by mitigating mitochondrial dysfunction mediated

Chandan Chauhan1, Ravinder K Kaundal1

  • 1Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP- 226002, India.

Mitochondrion
|August 20, 2026
PubMed

Insights

4-Octyl itaconate (4-OI) shows neuroprotection in stroke models by reducing oxidative stress and cell death. It activates the Nrf2 pathway, offering a promising therapeutic strategy for cerebral ischemia/reperfusion injury.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Ischemic stroke presents a significant unmet therapeutic need, characterized by oxidative stress, mitochondrial dysfunction, blood-brain barrier damage, and neuronal death.
  • Cerebral ischemia/reperfusion (I/R) injury models, including middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R), are crucial for studying stroke.
  • 4-Octyl itaconate (4-OI) is recognized for its antioxidant properties, but its role in cerebral I/R injury was previously unexplored.

Purpose of the Study:

  • To investigate the neuroprotective effects of 4-Octyl itaconate (4-OI) in models of cerebral ischemia/reperfusion (I/R) injury.
  • To elucidate the underlying mechanisms of 4-OI's action, focusing on oxidative stress, mitochondrial function, apoptosis, and ferroptosis.
  • To evaluate the role of the Nrf2 pathway in mediating the protective effects of 4-OI.

Main Methods:

  • Utilized middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models to simulate cerebral I/R injury.
  • Administered 4-Octyl itaconate (4-OI) and assessed neuronal survival, neurological outcomes, oxidative damage, and mitochondrial function.
  • Investigated intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and neuronal apoptosis.
  • Analyzed the modulation of the Nrf2/HO-1/SLC7A11/GPX4 axis, lipid peroxidation, and ferroptosis.
  • Employed pharmacological inhibition of Nrf2 using ML-385 and molecular docking to study the Keap1-Nrf2 interaction.

Main Results:

  • 4-Octyl itaconate (4-OI) treatment significantly improved neuronal survival and neurological outcomes in MCAO/R and OGD/R models.
  • 4-OI reduced oxidative damage, attenuated intracellular and mitochondrial ROS, restored mitochondrial membrane potential, and inhibited neuronal apoptosis.
  • 4-OI suppressed lipid peroxidation and ferroptosis by modulating the Nrf2/HO-1/SLC7A11/GPX4 axis, also protecting the blood-brain barrier (BBB).
  • Pharmacological inhibition of Nrf2 abolished 4-OI's protective effects, confirming Nrf2 activation's essential role.
  • Molecular docking indicated favorable binding of 4-OI to Keap-1, suggesting Nrf2 activation via Keap1-Nrf2 interaction inhibition.

Conclusions:

  • 4-Octyl itaconate (4-OI) confers significant neuroprotection against cerebral I/R injury.
  • The protective mechanisms involve activating the Nrf2 pathway, reducing oxidative stress, and suppressing ferroptotic and apoptotic cell death.
  • 4-OI represents a promising therapeutic candidate for cerebral I/R injury, targeting the Nrf2-mediated ferroptosis pathway.
Keywords:
4-OIApoptosisBBBFerroptosisIschemic strokeMitochondrial impairmentNrf2/Keap-1 pathway

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