Oxidative Medicine and Cellular Longevity

Review Article

Crosstalk between Oxidative Stress and Ferroptosis/Oxytosis in Ischemic Stroke: Possible Targets and Molecular Mechanisms

Table 1

Summary of molecular targets.


Molecular targets		Changes in ischemic stroke	Role in crosstalk between oxidative stress and ferroptosis/oxytosis	Clinical implications	References

Molecular players in peroxide production	Glutamate	Extracellular glutamate accumulation	A natural trigger which inhibits the cystine/glutamate X_C^- antiporter system and promotes oxidative stress and ROS production	Glutamate-induced HT22 hippocampal cell death is an established model system to study ferroptosis/oxytosis	[18, 24, 26, 51, 57, 69, 75]
	Fe²⁺	Excessive intracellular Fe²⁺	Fe²⁺ induces the increase of ROS by three ways: the Haber-Weiss chemical reaction, catalyzing lipid peroxidation, and important component of the catalytic subunit of LOX	Iron chelators deferoxamine can prevent ROS production and delay neuronal death	[38, 39, 46, 47, 82, 83, 146]
	ROS generation	Excessive ROS generation	The key molecular which leads to the production of lipid peroxidation	The target of antioxidants	[4, 26, 28, 77, 82, 84–86]
	Ca²⁺	Intracellular Ca²⁺ increase	Ca²⁺ is associated with ROS production and lipid peroxidation	Compounds that reduce Ca²⁺ influx can protect cell erastin-induced ferroptosis	[3, 27, 85, 87, 88, 90]
	Lipid peroxidation and LOX	Significant increase of lipid peroxidation	Lipid peroxidation is the main consequence of ROS-mediated brain injury and the key driving force of ferroptosis. LOX is a very important enzyme in the production of lipid peroxides	LOX inhibitors block glutamate toxicity and reduce neuronal ferroptosis and infarct size	[17, 23, 92, 93, 96, 97, 99]
	ATF4	ATF4 overexpression	ATF4, as a predecessor transcription factor of oxidative stress in neurons, drives the expression of presumed ferroptotic genes, including Chac1, Trb3, Chop, CARS, and the xCT cystine antiporter	ATF4 knockdown protects adult rats from stroke-induced injury	[53, 56, 120–124]

Molecular players in antioxidant depletion	X_C^-, GSH, GPX4	GPX4 and X_C^- inhibition, GSH depletion	Ultimately resulting in lipid peroxide accumulation and ferroptosis	TAT SelPep (a peptide containing selenocysteine) inducing GPX4 expression reduces the size of focal postischemic infarcts	[19, 26, 35, 102, 103, 105–107]
Molecular players in antioxidant depletion	Nrf2	Nrf2 activation	Nrf2 induces the transcription of proteins and enzymes, which are responsible for preventing lipid peroxidation and ferroptosis	Taraxasterol protects hippocampal neurons from damage due to oxygen glucose deprivation by activating the Nrf2 signaling pathway	[52, 130–132, 135–137, 139]