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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE278716 | GEO | 2025/01/06

REPOSITORIES: GEO

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Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent overaccumulation of lipid peroxides. It can be prevented by cellular mechanisms such as GPX4-mediated elimination of the lipid peroxides at the cost of glutathione (GSH). Since originally being discovered as a property of RAS-mutant cancer cells, ferroptosis has been shown to be regulated by several important oncogenes and tumor suppressors. In particular, LIFR, the receptor of the pleiotropic cytokine LIF, has recently been shown to be required for ferroptosis, as loss of Lifr in mouse liver tumor confers the cells resistance to ferroptosis. In this study, however, we found that the LIFR-targeting drugs, EC330 and EC359, are potent inducers of ferroptosis, thus reflecting an interesting “gain-of-function” effect of EC330/EC359 on LIFR-associated ferroptosis. Treatment of various types of cells with EC330/EC359 causes a rapid nonapoptotic cell death with characteristic morphology of ferroptosis, which can be inhibited by iron chelator (DFO) and lipid ROS scavenger (Fer-1), but not pan-caspase inhibitor (z-VAD-fmk). Consistent with previous observations, the efficiency of EC330/EC359 appears to be correlated with the expression levels of LIF and LIFR. RNA-seq analysis showed that the EC330/EC359 treatment leads to (i) a gene expression profile highly resembling that of RSL3, the GPX4-targeting ferroptosis inducer, and (ii) a specific decrease of expression of a few gene encoding membrane-located proteins, especially those located on the mitochondria (e.g., TOMM6 and COX14), implying defects in cellular/mitochondrial membrane functions. Indeed, transmission electron microscopy imaging of the EC330/EC359-treated cells shows shrunken mitochondria and loss of mitochondrial cristae. EC330/EC359 also decreases the activity of GPX4 in the cells to the level comparable with RSL3; meanwhile, the intracellular level of GSH is also decreased, and thus GPX4 inactivation and GSH depletion may jointly disable the cells to eliminate the toxic lipid peroxides. Lastly, although the STAT3 and AKT signaling pathways downstream of LIFR are inhibited by EC330/EC359, inhibition of these pathways per se can only induce non-ferroptotic cell death, suggesting that the EC330/EC359-induced ferroptosis is independent of these downstream pathways; the LIFR-NFkB-LCN2 axis discovered recently in mouse liver tumor cells might not explain the EC330/EC359-induced ferroptosis either, because LCN2 is not detectable in the herein used cell lines. Taken together, these results reveal an unexpected role of the LIFR-targeting drugs EC330/EC359 as potent inducer of ferroptosis and, in combination with previous studies, suggest that there could be either unknown mechanism for the LIFR-associated ferroptosis or unknown target for EC330/EC359 to effect the ferroptosis induction.

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

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