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Objective <p>Electroacupuncture has been shown to play a neuroprotective role following ischemic stroke, but the underlying mechanism remains poorly understood. Ferroptosis&#xa0;has been shown to&#xa0;play a key role in the injury process. In the present study, we wanted to explore whether electroacupuncture&#xa0;could inhibit ferroptosis by promoting nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation.</p> Methods <p>The ischemic stroke&#xa0;model was established by middle cerebral artery occlusion/reperfusion (MCAO/R) in adult rats.&#xa0;These rats have been randomly divided into&#xa0;the EA + MCAO/R group, the MCAO/R group,&#xa0;the EA + MCAO/R + Brusatol group (the&#xa0;inhibitor of Nrf2), and the EA + MCAO/R + DMSO group,&#xa0;and the Sham group. The EA + MCAO/R group, EA + MCAO/R + Brusatol group, and the EA + MCAO/R + DMSO group&#xa0;received&#xa0;EA intervention 24&#xa0;h after modeling&#xa0;for&#xa0;7 consecutive days. The behavioral function&#xa0;was evaluated by Neurologic severity&#xa0;score (NSS), Garcia score, Foot-fault Test, and Rotarod Test. The infarct volume was detected&#xa0;by TTC staining, and the neuronal damage was observed by Nissl staining. The levels of Fe<sup>2+</sup>, reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured by ELISA. The immunofluorescence and Western blotting were used to detect the expression of Total Nrf2, p-Nrf2, Nuclear Nrf2, and Cytoplasmic Nrf2, and the essential ferroptosis proteins, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) and ferritin heavy chain 1 (FTH1). The mitochondria were observed by transmission electron microscopy (TEM).</p> Results <p>Electroacupuncture improved neurological deficits in rats model of MCAO/R, decreased the brain infarct volume, alleviated neuronal damage, inhibited the Fe<sup>2+</sup>, ROS, and MDA accumulation, increased SOD levels, increased the expression of GPX4, SLC7A11 and FTH1, and rescued injured mitochondria. Especially, we found that the electroacupuncture up-regulated the expression of Nrf2, and promoted phosphorylation of&#xa0;Nrf2 and nuclear translocation, However, Nrf2 inhibitor&#xa0;Brusatol reversed the neuroprotective effect of electroacupuncture.</p> Conclusion <p>Electroacupuncture&#xa0;can&#xa0;alleviate cerebral I/R injury-induced ferroptosis by promoting Nrf2 nuclear translocation. It is expected that these data will provide novel insights into the mechanisms of electroacupuncture&#xa0;protecting against cerebral I/R injury and potential targets underlying ferroptosis in the stroke.</p> Graphical Abstract <p></p>

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Electroacupuncture attenuates ferroptosis by promoting Nrf2 nuclear translocation and activating Nrf2/SLC7A11/GPX4 pathway in ischemic stroke

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月4日

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  • Xi-chen Yang,
  • Ya-ju Jin,
  • Rong Ning,
  • Qiu-yue Mao,
  • Peng-yue Zhang,
  • Li Zhou,
  • Cheng-cai Zhang,
  • Yi-chen Peng,
  • Na Chen

摘要

Objective

Electroacupuncture has been shown to play a neuroprotective role following ischemic stroke, but the underlying mechanism remains poorly understood. Ferroptosis has been shown to play a key role in the injury process. In the present study, we wanted to explore whether electroacupuncture could inhibit ferroptosis by promoting nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation.

Methods

The ischemic stroke model was established by middle cerebral artery occlusion/reperfusion (MCAO/R) in adult rats. These rats have been randomly divided into the EA + MCAO/R group, the MCAO/R group, the EA + MCAO/R + Brusatol group (the inhibitor of Nrf2), and the EA + MCAO/R + DMSO group, and the Sham group. The EA + MCAO/R group, EA + MCAO/R + Brusatol group, and the EA + MCAO/R + DMSO group received EA intervention 24 h after modeling for 7 consecutive days. The behavioral function was evaluated by Neurologic severity score (NSS), Garcia score, Foot-fault Test, and Rotarod Test. The infarct volume was detected by TTC staining, and the neuronal damage was observed by Nissl staining. The levels of Fe2+, reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured by ELISA. The immunofluorescence and Western blotting were used to detect the expression of Total Nrf2, p-Nrf2, Nuclear Nrf2, and Cytoplasmic Nrf2, and the essential ferroptosis proteins, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) and ferritin heavy chain 1 (FTH1). The mitochondria were observed by transmission electron microscopy (TEM).

Results

Electroacupuncture improved neurological deficits in rats model of MCAO/R, decreased the brain infarct volume, alleviated neuronal damage, inhibited the Fe2+, ROS, and MDA accumulation, increased SOD levels, increased the expression of GPX4, SLC7A11 and FTH1, and rescued injured mitochondria. Especially, we found that the electroacupuncture up-regulated the expression of Nrf2, and promoted phosphorylation of Nrf2 and nuclear translocation, However, Nrf2 inhibitor Brusatol reversed the neuroprotective effect of electroacupuncture.

Conclusion

Electroacupuncture can alleviate cerebral I/R injury-induced ferroptosis by promoting Nrf2 nuclear translocation. It is expected that these data will provide novel insights into the mechanisms of electroacupuncture protecting against cerebral I/R injury and potential targets underlying ferroptosis in the stroke.

Graphical Abstract