Neural Regeneration Research ›› 2021, Vol. 16 ›› Issue (3): 561-566.doi: 10.4103/1673-5374.293157

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Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4

Bao-You Fan1, #, Yi-Lin Pang1, #, Wen-Xiang Li1, #, Chen-Xi Zhao1, Yan Zhang1, Xu Wang1, Guang-Zhi Ning1, Xiao-Hong Kong2, Chang Liu2, Xue Yao1, *, Shi-Qing Feng1, *   

  1. 1 International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; 2 School of Medicine, Nankai University, Tianjin, China
  • Online:2021-03-15 Published:2020-12-17
  • Contact: Xue Yao, Ph.D, xueyao@tmu.edu.cn; Shi-Qing Feng, PhD, MD, sqfeng@tmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81672171 (to XY), 81972074 (to XY), 81930070 (to SQF), 81620108018 (to SQF), and 81772342 (to GZN); the National Key R&D Program of China, No. 2019YFA0112100 (to SQF); the Natural Science Foundation of Tianjin of China, No. 19JCZDJC34900 (to XY).

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Abstract: Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury. High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma. In this study, we established an oligodendrocyte (OLN-93 cell line) model of ferroptosis induced by RSL-3, an inhibitor of glutathione peroxidase 4 (GPX4). RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde. RSL-3 also inhibited the main anti-ferroptosis pathway, i.e., SLC7A11/glutathione/glutathione peroxidase 4 (xCT/GSH/GPX4), and downregulated acyl-coenzyme A synthetase long chain family member 4. Furthermore, we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis. Liproxstatin-1 was more potent than edaravone or deferoxamine. Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation, but also restored the expression of GSH, GPX4 and ferroptosis suppressor protein 1. These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes, and that liproxstatin-1 is a potent inhibitor of ferroptosis. Therefore, liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases.

Key words: cell death, central nervous system, factor, ferroptosis, oligodendrocyte, oxidation, pathway, repair, spinal cord injury