Ferroptosis Mechanisms in Neurotrauma and Recovery

Ferroptosis is an iron-dependent form of regulated cell death distinguished by the unchecked accumulation of lipid peroxides, a collapse of antioxidant defences and consequent membrane damage. In the context of neurotrauma—such as traumatic brain injury, spinal cord contusion and haemorrhagic stroke—iron liberated from disrupted vasculature and dysfunctional mitochondria catalyses the formation of reactive oxygen species, driving lipid peroxidation and neuronal demise. This process exacerbates blood–brain barrier breakdown, neuroinflammation and oedema, thereby amplifying secondary injury. Concurrently, ferroptotic sensitivity is modulated by the system Xc− cystine–glutamate antiporter, glutathione peroxidase 4 and parallel defence systems such as ferroptosis suppressor protein 1. Advances in understanding these pathways have revealed targets for pharmacological and biological interventions that attenuate oxidative stress, preserve neuronal integrity and promote functional recovery.

Research from Nature Portfolio

Recent studies have demonstrated that oxidative insults in neuronal models induce ferroptosis in conjunction with mitochondrial dysfunction. In one cellular investigation, exposure of neuronal-like cells to peroxides triggered iron-mediated lipid peroxidation, loss of mitochondrial membrane potential and activation of stress kinases, all of which were reversed by ferroptosis inhibitors and iron chelators, underscoring the interplay between mitochondrial health and ferroptotic execution. In an in vivo model of controlled cortical impact, upregulation of a secreted neuropeptide prior to injury suppressed key lipid-modifying enzymes, reduced lipid peroxidation substrates and limited neuronal ferroptosis, leading to improved motor and cognitive outcomes. This work highlights the potential of endogenous regulators in mitigating ferroptosis after acute brain injury.

Ferroptosis Mechanisms in Neurotrauma and Recovery publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in neurotrauma and recovery across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A regulated cell-death pathway driven by iron-catalysed lipid peroxidation and distinct from apoptosis or necrosis.

Lipid peroxidation: Oxidative degradation of membrane lipids leading to loss of membrane integrity and cell death.

Reactive oxygen species (ROS): Highly reactive molecules derived from oxygen that can damage proteins, lipids and DNA.

System Xc−: A cell-surface antiporter that imports cystine in exchange for glutamate, fuelling glutathione synthesis.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that reduces lipid hydroperoxides and is a central brake on ferroptosis.

References

1. Oroxin A alleviates early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation. Journal of Neuroinflammation (2024).
2. Broadening horizons: ferroptosis as a new target for traumatic brain injury. Burns & Trauma (2024).
3. Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells. Scientific Reports (2018).
4. Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway. CNS Neuroscience & Therapeutics (2021).
5. Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury. Nature Communications (2021).