br Acknowledgments We apologize to the researchers who

Acknowledgments We apologize to the researchers who were not referenced due to space limitations. We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (R01GM115366, R01CA160417, and R01CA211070), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the Natural Science Foundation of Guangdong Province (2016A030308011), the National Natural Science Foundation of China (31671435 and 81772508), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He’s Academician Workstation of New Medicine and Clinical Translation (2017), and the International Scientific and Technology Cooperation Program of China (2015DFA31490). GK is supported by the Ligue contre le Cancer Comité de Charente-Maritime (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière, the Searave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).
Introduction Spinal cord injury (SCI) affects tens of thousands of individuals each year (Wu et al., 2012). The pathophysiology of SCI involves complex molecular and cellular events, and can be divided into primary and secondary injury (Fang et al., 2017, van Niekerk et al., 2016). Currently no effective treatment is available, indicating that the crucial mechanisms that contributing to tissue damage and regenerative failure are still elusive (Fink and Cafferty, 2016). Primary injury may cause immediate cell death, whereas secondary injury is amenable to therapeutic strategies to prevent further cell loss (Ropper and Ropper, 2017, Xue et al., 2013). How to control the multiple cascades of injury-induced molecular and cellular changes leading to secondary injury is a key issue to develop effective therapies in promoting recovery after SCI. The modes of cell death in SCI have been a HMP Linker of intense discussion. Apoptosis and necroptosis are known to contribute to cell damage of acute SCI (Gao et al., 2016, Liu et al., 2015a, Zhang et al., 2012), whereas autophagy seems to have a beneficial effect in SCI (He et al., 2016, Wang et al., 2016). However, other cell death pathway, such as ferroptosis, have not been characterized in the context of SCI. Ferroptosis is recently found as an iron-dependent non-apoptotic cell death (Dixon et al., 2012, Lachaier et al., 2014, Louandre et al., 2013). The death phenotype of ferroptosis is distinct from other cell mortalities, such as apoptosis and necroptosis (Speer et al., 2013). The characteristic include mitochondria shrinkage in ferroptosis can be detected morphologically by electron microscope (Linkermann et al., 2014). Glutathione peroxidase 4 (GPX4), a lipid repair enzyme, is the central regulator of ferroptosis (Conrad and Friedmann Angeli, 2015, Imai et al., 2017, Sakai et al., 2017, Yang et al., 2014). System Xc-light chain (xCT) is a glutamate/cysteine antiporter and a regulator of ferroptosis. xCT increases the intracellular cysteine pool, which is a precursor for glutathione synthesis (Yu et al., 2017). Ferroptosis is induced by failure of membrane lipid repair, resulting in the accumulation of reactive oxygen species (ROS) on the membrane lipids (Cardoso et al., 2017, Conrad and Friedmann Angeli, 2015, Imai et al., 2017). Glutathione (GSH) is a tripeptide cellular antioxidant which protects lipids, DNA and proteins from the oxidative damage (Gao et al., 2015). The level of GSH intracellular is influenced by the expression of xCT (Schott et al., 2015). 4-hydroxynonenal (4HNE) is the lipid ROS marker in lipid peroxidation reactions (Dixon et al., 2012, Li et al., 2017, Linkermann et al., 2014). Suppression of lipid peroxidation halts the cell death process of ferroptosis (Gaschler and Stockwell, 2017). Two major factors that trigger ferroptosis in vitro in cancer cells and brain slices are iron overload and lipid ROS (Basit et al., 2017, Jiang et al., 2015), which have been reported in SCI. In fact, the traumatic SCI leads to immediate hemorrhage and ROS accumulation (Xiao et al., 2015), and hemorrhage increases iron load at the injury site (Hao et al., 2017). Ferroptotic cell death could also be induced by glutamate, which is known elevated after SCI and indicated as glutamate-excitotoxicity (Dixon et al., 2014, Liu et al., 2015b, Maher et al., 2017). Therefore, we speculate that ferroptosis occurs in SCI and contributes to secondary injury. If this is true, inhibition of ferroptosis should reduce the secondary injury and enhance the spinal cord repair.