A cholesterol precursor mediates sensitivity to cell death by ferroptosis

A cholesterol precursor mediates sensitivity to cell death by ferroptosis
Identification and impact of DHCR7 deficiency on ferroptosis. a, Schematic of the identification of Dhcr7 as a proferroptotic gene, using CRISPR-KO library and GPX4 inhibition. b, Volcano plot of sgRNA enriched in cells selected with RSL3 compared with untreated control cells. c, Immunoblot (IB) analysis of DHCR7 and key ferroptosis regulators, namely, FSP1, ACSL4 and GPX4 in cells expressing an sgRNA targeting DHCR7 and EGFP. Values represent mean ± s.d. of ratio of protein of interest in relation to β-actin, n = 3 independent experiments. d, Relative quantification of 7-DHC and cholesterol concentrations in HT1080 cell lines stably transduced with a vector expressing Cas9 and a sgRNA targeting DHCR7 and EGFP as a control. e, Assessment of de novo cholesterol biosynthesis, by means of the quantification of 13C-cholesterol originating from 13C-glucose in HT1080 cell expressing sgRNA targeting DHCR7 and EGFP as control. Data are the mean ± s.d. of n = 3 wells of a 6-well plate from one representative experiment (d,e). f, Dose-dependent toxicity of the ferroptosis inducers RSL3, ML210 and FIN56 in HT1080 cell lines stably transduced with a vector expressing Cas9 and an sgRNA targeting DHCR7 and EGFP as a control. Cell viability was monitored using Alamar blue after 48 h (f) and represented as the mean ± s.d. of triplicates from one representative of two independent experiments (f). *P < 0.05; two-way analysis of variance (ANOVA) (d–f). Credit: Nature (2024). DOI: 10.1038/s41586-023-06878-9

A team of scientists from the University of Ottawa and researchers from other universities and research centers around the world has discovered that 7-dehydrocholesterol (7-DHC) is an endogenous suppressor of ferroptosis, which could have important implications for the treatment of cell death-related diseases.

The findings are published in the journal Nature.

Ferroptosis is a form of cell death that is characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS) in cells. It is a regulated process that is distinct from other forms of cell death, such as apoptosis and necrosis.

The researchers identified a pro-ferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected pro-survival function of its substrate, 7-dehydrocholesterol (7-DHC).

“The pro-survival function of 7-DHC was surprising because it more readily forms peroxides than essentially all other lipids, and lipid peroxide formation is generally associated with ferroptosis,” explains Derek Pratt, a professor who holds the University Research Chair in Free Radical Chemistry at the Department of Chemistry and Biomolecular Sciences of uOttawa’s Faculty of Science.

Professor Pratt and his students Omkar Zilka (Ph.D.), Emily Schaefer (MSc) and Ife Ekpo (BSc) studied how accumulation of 7-DHC could slow ferroptosis, finding that while it is oxidized more quickly than other lipids, the peroxides formed from it are not as toxic to the cell.

The researchers used a combination of genetic and pharmacological approaches to investigate the role of DHCR7 and 7-DHC in ferroptosis. They used CRISPR-Cas9 gene editing to knock out DHCR7 in human cells and found that this increased sensitivity to ferroptosis.

They also showed that reconstitution of DHCR7 activity in these cells restored resistance to ferroptosis. Furthermore, they found that treatment with exogenous 7-DHC protected cells from ferroptosis, while inhibition of 7-DHC synthesis sensitized cells to ferroptosis. These results led the researchers to conclude that 7-DHC is an endogenous suppressor of ferroptosis.

“Perhaps the most exciting aspect is that it would appear that some cancers upregulate 7-DHC to escape ferroptosis, suggesting it may be targeted for ,” says Professor Pratt.

This study highlights the dual role of 7-DHC in ferroptosis, acting both as a pro-survival shield and as an advantage for in Burkitt’s lymphoma. The unexpected anti-ferroptosis activity of 7-DHC provides new insights into the intrinsic mechanisms by which escape ferroptosis, paving the way for potential therapeutic strategies targeting this metabolic adaptation.

More information:
Florencio Porto Freitas et al, 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis, Nature (2024). DOI: 10.1038/s41586-023-06878-9

A cholesterol precursor mediates sensitivity to cell death by ferroptosis (2024, January 31)
retrieved 1 February 2024
from https://phys.org/news/2024-01-cholesterol-precursor-sensitivity-cell-death.html

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