Internal medicine

Enzyme

Proteases

Stroke (engine)

Ischemia

Engineering

Apoptosis

Chemistry

Immunology

Brain ischemia

Thrombin

Arachidonic acid

Programmed cell death

Cancer research

Biochemistry

Medicine

Mechanical engineering

Platelet

Pharmacology

Signal Transduction and Targeted Therapy

Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.

Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion