Journal
FEBS OPEN BIO
Volume 11, Issue 8, Pages 2118-2126Publisher
WILEY
DOI: 10.1002/2211-5463.13203
Keywords
Akt; Nrf2; HO-1; Erastin; ferroptosis; lipoxin A4; primary spinal cord neurons; spinal cord injury
Categories
Funding
- Key scientific research project plan of Henan University [19A320003]
- Scientific and Technological Project of XinXiang City [CXGG17031]
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This study demonstrated that LXA4 exerts a neuroprotective effect in Erastin-induced ferroptosis of primary spinal cord neurons by activating the Akt/Nrf2/HO-1 signaling pathway, providing novel insights into the mechanisms of action of LXA4 in ferroptosis and indicating its potential as a therapeutic agent for SCI.
Ferroptosis is an iron-dependent programmed cell death, which participates in the pathogenesis of spinal cord injury (SCI). Our previous study has revealed that Lipoxin A4 (LXA4) exerts a protective role in SCI. Here, we investigated whether LXA4 can protect SCI through inhibiting neuronal ferroptosis. We treated primary spinal cord neurons with Erastin (ferroptosis activator) to induce ferroptosis. Erastin treatment reduced cell viability and enhanced cell death of primary spinal cord neurons, which was rescued by ferrostatin-1 (ferroptosis inhibitor). Moreover, Erastin repressed glutathione peroxidase 4 (GPX4) expression and the levels of glutathione and cysteine in primary spinal cord neurons. Erastin also enhanced the expression of ferroptosis biomarkers (PTGS2 and ACSL4) and the levels of reactive oxygen species (ROS) in primary spinal cord neurons. The influence conferred by Erastin was effectively abolished by LXA4 treatment. Furthermore, LXA4 enhanced the protein expression of p-AKT, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and haem-oxygenase-1 (HO-1) in primary spinal cord neurons. LXA4-mediated inhibition of ferroptosis of primary spinal cord neurons was prohibited by LY294002 (AKT inhibitor), brusatol (Nrf2 inhibitor) or zinc protoporphyrin (HO-1 inhibitor). In conclusion, this work demonstrated that LXA4 exerted a neuroprotective effect in Erastin-induced ferroptosis of primary spinal cord neurons by activating the Akt/Nrf2/HO-1 signaling pathway. Thus, this work provides novel insights into the mechanisms of action of LXA4 in ferroptosis of primary spinal cord neurons and indicates that LXA4 may be a potential therapeutic agent for SCI.
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