The ferroptosis activity is associated with neurological recovery following chronic compressive spinal cord injury

Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium state of neurological dysfunction.Ferroptosis is a crucial pathological process in many neurodegenerative diseases;however,its role in chro nic compressive spinal cord injury remains unclear.In this study,we established a chronic compressive spinal cord injury rat model,which displayed its most severe behavioral and electrophysiological dysfunction at 4 wee ks and partial recovery at 8 weeks after compression.Bulk RNA sequencing data identified enriched functional pathways,including ferroptosis,presynapse,and postsynaptic membrane activity at both 4 and 8 wee ks following chro nic compressive spinal co rd injury.Tra nsmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression.Ferro ptosis activity was negatively correlated with behavioral score.Immunofluorescence,quantitative polymerase chain reaction,and western blotting showed that expression of the anti-ferroptosis molecules,glutathione peroxidase 4(GPX4) and MAF BZIP transcription factor G(MafG),in neuro ns was suppressed at 4 weeks and upregulated at 8 weeks following spinal co rd compression.There was a positive correlation between the expression of these two molecules,suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury.In conclusion,our study determined the genome-wide expression profile and fe rroptosis activity of a consistently compressed spinal cord at different time points.The results showed that anti-fe rroptosis genes,specifically GPX4 and MafG,may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury.These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.

Dysregulation of glutathione synthesis in liver disease

Glutathione(GSH),a tripeptide that is present in all mammalian tissues,is especially highly concentrated in the liver.GSH synthesis occurs via two adenosine triphosphate(ATP)-requiring enzymatic steps:the first is rate-limiting,catalyzed by glutamate-cysteine ligase,generates g-glutamylcysteine from gluta-mate and cysteine;the second is catalyzed by GSH synthetase,generates GSH from g-glutamylcysteine and glycine.GSH defends against oxidative stress,participates in detoxification of xenobiotics,de-termines the redox status of the cell,and regulates vital processes such as growth and apoptosis.Hepatic GSH plays a central role in the interorgan GSH homeostasis because sinusoidal efflux of hepatic GSH determines plasma GSH level.In liver diseases GSH homeostasis is perturbed by multiple mechanisms.Hepatic GSH biosynthesis is impaired in cholestatic liver injury,endotoxemia,and fibrotic injury largely because the expression of the GSH synthetic enzymes falls.Lower hepatic GSH level further exacerbates and perpetuates ongoing liver injury.However,in hepatocellular carcinoma GSH synthetic enzymes are upregulated and this may play a role in chemoresistance.This review focuses on the current under-standing of hepatic GSH synthesis in health and disease.