Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Ischemic stroke is a leading cause of death and disability, particularly in the elderly.
• Current interventions for ischemic stroke primarily focus on clot removal, with the precise mechanisms of neuronal death remaining under investigation.
• Ferroptosis, a distinct form of regulated cell death, is emerging as a significant contributor to ischemic injury in various organs.

Purpose of the Study:

• To elucidate the role of thrombin in initiating ferroptosis during ischemic stroke.
• To identify key molecular players, including ACSL4, involved in thrombin-induced ferroptosis.
• To evaluate the therapeutic potential of targeting the thrombin-ACSL4 axis for mitigating ischemic stroke damage.

Main Methods:

• Utilized an unbiased multi-omics approach (genomics, proteomics, lipidomics) in rodent models of middle cerebral artery occlusion (MCAO).
• Investigated the function of thrombin and acyl-CoA synthetase long-chain family member 4 (ACSL4) in ferroptotic signaling.
• Employed genetic and pharmacological inhibition strategies to block the identified pathway in vitro and in vivo ischemia models.

Main Results:

• Identified thrombin and ACSL4 as key mediators of ferroptosis in ischemic stroke.
• Demonstrated that thrombin promotes arachidonic acid mobilization and esterification via ACSL4, leading to ferroptotic cell death.
• Showcased that inhibiting thrombin or ACSL4 significantly attenuated neuronal injury and improved outcomes in experimental stroke models.

Conclusions:

• The serine protease thrombin plays a critical role in instigating ferroptotic signaling during ischemic stroke.
• The thrombin-ACSL4 axis represents a novel and promising therapeutic target for reducing ferroptotic neuronal death in ischemic stroke.
• Targeting this pathway could offer a new strategy to protect brain tissue following stroke.