Prok2/PKR signaling regulates ferroptosis after spinal cord injury

Abstract

Spinal cord injury (SCI) is a severe traumatic condition that often results in significant disability and death. SCI also causes secondary damage in the acute phase due to neuronal cell death. SCI has been linked to ferroptosis, a new type of cell death. Prokineticin 2 (Prok2) and its receptors (PKR1 and PKR2) are involved in various physiological processes and have been shown to regulate ferroptosis in traumatic brain injury. However, the role of Prok2/PKR signaling in SCI-induced ferroptosis and neurodegeneration is unclear. In this study, we examined the expression of Prok2/PKR signaling pathway components and the function of the Prok2/PKR signaling pathway in a rat model of contusion SCI. We found that the expression of Prok2 and PKRs decreased and was subsequently restored after SCI and that Prok2 and PKRs were localized in neurons in the anterior horn of the spinal cord. We also found that the expression levels of the ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were altered after SCI, suggesting that neurons underwent ferroptosis. Furthermore, we demonstrated that upregulation of Prok2 by intraperitoneal injection of recombinant human Prok2 protein inhibited ferroptosis and reduced neurodegeneration after SCI and that this effect was mediated by PKR1 and PKR2, as silencing these receptors with small interfering RNA (siRNA) reversed recombinant Prok2-mediated ferroptosis inhibition. Our study is the first to reveal that Prok2/PKR signaling plays antiferroptotic and neuroprotective roles in SCI, making it a potential target for SCI treatment.