4-Octyl itaconate attenuates cerebral ischemia reperfusion injury by mitigating mitochondrial dysfunction mediated neuronal apoptosis and ferroptosis via the Nrf2/HO-1/SLC7A11/GPX4 axis.

Abstract

Ischemic stroke is an unmet therapeutic need, characterised by excessive oxidative stress, mitochondrial impairment, blood-brain barrier (BBB) damage, and neuronal cell death. 4-Octyl itaconate (4-OI) is known for its promising antioxidant properties; however, its effects in cerebral ischemia/reperfusion (I/R) injury have not been previously explored. In this study, middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to mimic the cerebral I/R injury. Treatment with 4-OI significantly improved neuronal survival and neurological outcomes, reduced oxidative damage and mitochondrial dysfunction. Mechanistically, 4-OI markedly attenuated intracellular and mitochondrial ROS, restored mitochondrial membrane potential, and inhibited neuronal apoptosis. Furthermore, 4-OI treatment exerts its neuroprotective effect by suppressing lipid peroxidation and modulating the Nrf2/HO-1/SLC7A11/GPX4 axis to inhibit ferroptosis and BBB damage. Pharmacological inhibition of Nrf2 using ML-385 abolished the effects of 4-OI, confirming the essential role of Nrf2 activation in mediating ferroptosis suppression. Additionally, molecular docking analysis revealed favourable binding of 4-OI to Keap-1, supporting a potential mechanism by which 4-OI impede the Keap1-Nrf2 interaction to promote Nrf2 activation. Collectively, these findings suggest that 4-OI confers Neuroprotection against I/R injury by activating Nrf2 pathway, reducing oxidative stress, and suppressing ferroptotic and apoptotic cell death. This study identifies 4-OI as a promising therapeutic candidate for cerebral I/R injury and highlights the Nrf2-mediated ferroptosis pathway as a potential target for neuroprotection.

Key Findings

• 4-Octyl itaconate (4-OI) treatment improves neuronal survival and neurological outcomes in cerebral ischemia/reperfusion injury models.
• 4-OI reduces oxidative damage, mitochondrial dysfunction, intracellular and mitochondrial ROS, and inhibits neuronal apoptosis.
• 4-OI activates the Nrf2/HO-1/SLC7A11/GPX4 axis, suppressing ferroptosis and blood-brain barrier damage, with Nrf2 activation essential for these effects.

Clinical Significance

Citation

Chauhan Chandan, Kaundal Ravinder K. 4-Octyl itaconate attenuates cerebral ischemia reperfusion injury by mitigating mitochondrial dysfunction mediated neuronal apoptosis and ferroptosis via the Nrf2/HO-1/SLC7A11/GPX4 axis. Mitochondrion. 2026-Aug-20.