Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway

Abstract

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.

Ferroptosis and ferritinophagy in diabetes complications

“…That is, tagitin C induces ferroptosis through the activation of the PERK-NRF2-HO-1 signaling pathway mediated by ER [ 74 ]. In addition, there are other pathways related to NRF2 that regulate ferroptosis: GSK-3β/NRF2 signaling pathway [ 75 ], Akt/NRF2/HO-1 signaling pathway [ 76 ], Keap1/NRF2-ARE signaling pathway [ 77 ], and AMPK-NRF2 signaling pathway [ 78 ], all of which play a regulatory role on ferroptosis in specific cells.…”

Ferroptosis: A Novel Therapeutic Direction of Spinal Cord Injury

“…These findings might lead to a novel therapeutic method for SCI. By stimulating the AKT/Nrf2/HO-1 signaling pathway, the anti-inflammatory mediator lipoxin A4 can reduce ferroptosis in spinal cord neurons [ 77 ]. Similarly, syringic acid [ 75 ], proanthocyanidins [ 73 ], and zinc [ 74 ] all reversed ferroptosis to varying degrees by activating the Nrf2/HO-1 pathway.…”

L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells

“…On the other side, our previous results indicated that L-F001 could activate Nrf-2/HO-1 signaling (Luo et al, 2017 ), we also found that Nrf2/HO-1 signaling is activation under RSL-3 treatment rather than downregulation (Peng et al, 2021 ). Furthermore, some research demonstrated that many active compounds exhibit protection through further upregulation of Nrf2/HO-1 signaling (Gou et al, 2020 ; Wei et al, 2021 ; Fu et al, 2022 ), compared to the already increased Nrf2 signaling. Therefore Nrf2/HO-1 signaling activation might be an important part in L-F001 anti-ferroptosis role.…”