Cerebral Ischemia–Reperfusion Injury: Unraveling the Mitophagy–Oxidative Stress Axis for Neuroprotective Strategies

Mar 14, 2026International journal of molecular sciences

Brain Damage from Blood Flow Return: Understanding Cell Cleanup and Oxidative Stress for Protecting Nerves

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Abstract

Cerebral ischemia-reperfusion injury is a critical factor in neurological decline after ischemic stroke.

Cerebral ischemia-reperfusion injury involves complex interactions among multiple cellular pathways rather than isolated responses.
The relationship between mitophagy and oxidative stress plays a key role in regulating neuronal health.
Moderate oxidative stress can activate protective mitophagy, aiding in mitochondrial quality control and maintaining cellular balance.
Regulated mitophagy helps to reduce harmful reactive oxygen species by removing damaged mitochondria.
Dysregulation of mitophagy or oxidative stress may lead to increased mitochondrial dysfunction and neuronal injury.
Emerging therapies aim to modulate the mitophagy-oxidative stress interaction to enhance neuroprotection.

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Cerebral ischemia-reperfusion (I/R) injury is a major pathological contributor to neurological deterioration following ischemic stroke (IS) and remains a critical barrier to effective neuroprotection. Accumulating evidence indicates that cerebral I/R injury is driven not by isolated stress responses but by coordinated and dynamic interactions among multiple cellular pathways. Among these, the bidirectional crosstalk between mitophagy and oxidative stress has emerged as a central regulatory axis. Moderate oxidative stress can function as an adaptive signal, activating protective mitophagy through key pathways such as AMPK/ULK1 signaling and cardiolipin externalization, thereby facilitating mitochondrial quality control and maintaining cellular homeostasis. Conversely, appropriately regulated mitophagy limits excessive reactive oxygen species (ROS) production by removing dysfunctional mitochondria, forming a negative feedback mechanism. However, dysregulation or excessive activation of either process disrupts this balance, leading to a self-amplifying cycle of mitochondrial dysfunction and oxidative damage that exacerbates neuronal injury. This review systematically summarizes the molecular mechanisms governing the oxidative stress-mitophagy crosstalk in cerebral I/R injury, highlighting key signaling nodes and regulatory pathways that determine protective versus detrimental outcomes. Furthermore, we discuss emerging therapeutic strategies aimed at precisely modulating this axis in a spatiotemporal- and intensity-dependent manner. By integrating mechanistic insights with translational perspectives, this review provides a conceptual framework for developing targeted neuroprotective interventions based on coordinated regulation of mitochondrial quality control and redox homeostasis.

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Cerebral Ischemia–Reperfusion Injury: Unraveling the Mitophagy–Oxidative Stress Axis for Neuroprotective Strategies

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