PUM2 aggravates the neuroinflammation and brain damage induced by ischemia–reperfusion through the SLC7A11-dependent inhibition of ferroptosis via suppressing the SIRT1

Abstract

Cerebral ischemia–reperfusion (I/R) injury occurs due to the restoration of blood perfusion after cerebral ischemia, which results in the damage of the brain structures and functions. Unfortunately, currently there are no effective methods for preventing and treating it. The pumilio 2 (PUM2) is a type of RBPs that has been reported to participate in the progression of several diseases. Ferroptosis is reported to be involved in I/R injury. Whether PUM2 modulated I/R injury through regulating ferroptosis remains to be elucidated. The cerebral I/R models including animal middle cerebral artery occlusion/reperfusion (MCAO/R) model and oxygen–glucose deprivation/reperfusion (OGD/R)-induced cortical neuron injury cell model of were established and, respectively. RT-qPCR was applied for evaluating PUM2, SIRT1 and SLC7A11 expression. Western blot was employed for measuring the protein expression levels. The viability of cortical neurons was tested by MTT assay. The histological damage of the brain tissues was assessed by H&E staining. The level of PUM2 was boosted in both the brain tissues of the MCAO model and OGD/R-induced cortical neuron injury model. Silence of PUM2 alleviated MCAO-induced brain injury and decreased the death of PC12 cell exposed to OGD/R. PUM2 also aggravated the accumulation of free iron in MCAO mice and OGD/R-induced cortical neuron injury model. In addition, PUM2 suppressed SLC7A11 via inhibiting expression of SIRT1. Rescue assays unveiled that downregulation of SLC7A11 reversed PUM2 mediated neuroinflammation and brain damage induced by I/R. PUM2 aggravated I/R-induced neuroinflammation and brain damage through the SLC7A11-dependent inhibition of ferroptosis by suppressing SIRT1, highlighting the role of PUM2 in preventing or treating cerebral I/R injury.

The Critical Role of Sirt1 in Subarachnoid Hemorrhages: Mechanism and Therapeutic Considerations

“…Numerous studies have proposed the functions of Sirt1 in ferroptosis. Liu et al found that pumilio 2 (PUM2) aggravated the neuroinflammation and brain damage induced by ischemia–reperfusion through ferroptosis by inhibiting the Sirt1 [ 133 ]. Moreover, Li et al [ 134 ] proposed that Sirt1 upregulation attenuated ferroptosis levels in ischemic ischemic hypoxic–ischemic brain injury and improved learning and memory via the Nrf2/GPx4 signaling pathway.…”

The roles of sirtuins in ferroptosis

“… Liang et al (2023) showed that mitochondrial damage resulting from SIRT1 inactivation played an important role in ferroptosis caused by Epothilone B in schwann cells. Liu et al found identified that pumilio 2 (PUM2) promoted ferroptosis by inhibiting SIRT1/SLC7A11, aggravated neuroinflammation and brain damage induced by ischemia-reperfusion injury ( Liu et al, 2023 ). In addition, activation of SIRT1 and GPX4 by calorie restriction protects against the ferroptosis-caused kidney injury in the Sprague Dawley rat model of contrast-induced nephropathy ( Fang et al, 2021 ).…”

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

“…Ferritin also significantly reduces tau hyperphosphorylation and oxidative stress [ 113 ]. Accordingly, the role of the Tau protein is age-dependent in cerebral IRI [ 114 ], and Tau can promote iron transfer in aging-related ischemic stroke to mitigate ferroptosis [ 115 ]. Additionally, NCOA4 mediates the excessive degradation of ferritin caused by ferritinophagy during cerebral I/R followed by ferroptosis [ 116 ].…”

“…SLC7A11 mediates the synthesis of glutathione, which is available to GPX4 to reduce lipid peroxidation. However, PUM2 attenuates the inhibitory effect of SLC7A11 on ferroptosis by suppressing SIRT1 expression, thus exacerbating I/R-induced neuroinflammation and brain injury [ 114 ]. In tert-butyl-hydroxyperoxide-treated neurons, activation of the SSAT1/ALOX15 axis downregulated the expression of GPX4 and SLC7A11, which triggered neuronal death and worsened IRI [ 118 ].…”