Transcriptomic signatures of oxytosis/ferroptosis are enriched in Alzheimer's disease

Oxytosis/ferroptosis is a non-apoptotic regulated cell death pathway characterized by glutathione (GSH) depletion with consequent inhibition of the GSH-dependent enzyme GSH peroxidase 4 (Gpx4), activation of lipoxygenases (LOXs), production of reactive oxygen species (ROS) and mitochondrial dysfunction, that culminates in cell death. Most of these changes are observed with aging and exacerbated in Alzheimer's disease (AD). Furthermore, it has been shown that novel inhibitors of oxytosis/ferroptosis are protective in mouse models of aging and AD. One of the most potent of these inhibitors is the neuroprotective compound CMS121. The goal of the present study was to investigate the occurrence of oxytosis/ferroptosis in the AD brain by examining transcriptomic signatures of oxytosis/ferroptosis in multiple cellular and animal models of AD as well as in human AD brain samples. Our data show that different signatures of oxytosis/ferroptosis are enriched to varying extents in the brains of AD mice and human AD patients. https://doi.org/10.1186/s12915-025-02235-6 Overall design: We carried out a study of the whole transcriptome of mouse HT22 nerve cells in conditions of non-induced and induced oxytosis/ferroptosis in the absence and presence of 1uM CMS121. In cell culture, oxytosis/ferroptosis can be triggered by inhibiting cystine uptake via the cystine/glutamate antiporter system xc- with glutamate which subsequently depletes intracellular GSH. For this study, cells were harvested 6h after exposure to glutamate in the absence and presence of CMS121, prior to any cell death, and the whole RNA was isolated and sequenced.