COX-2/PGE2 Pathway Inhibits the Ferroptosis Induced by Cerebral Ischemia Reperfusion

Cerebral ischemia reperfusion (I/R) injury easily develops in ischemic stroke, resulting in more serious injury. Ferroptosis is involved in cerebral I/R injury, but the mechanism remains unclear. Prostaglandin E2 (PGE2) is potential to regulate ferroptosis. This study mainly explored the regulation effects of PGE2 on ferroptosis induced by cerebral I/R. We first detected PGE2 levels and ferroptosis status in 11 human brain tissues. Then, we induced a cerebral I/R animal model to examine ferroptosis status in cerebral I/R. We further injected a ferroptosis inhibitor to define the response of the PGE2 pathway to ferroptosis. Finally, we injected PGE2 and pranoprofen to explore the regulation of the cyclooxygenases 2 (COX-2)/PGE2 pathway on ferroptosis in cerebral I/R. We found that PGE2 release was correlated with the levels of reactive oxygen species, malondialdehyde, glutathione peroxidase 4, COX-2, and Spermidine/spermine N1-acetyltransferase 1. Ferroptosis can be induced by cerebral I/R, while inhibition of ferroptosis induced by cerebral I/R can inactivate PGE2 synthases, degrade enzyme, and parts of PGE2 receptors, and reduce cerebral infarct volume. In turn, PGE2 inhibited ferroptosis through the reduction of Fe