7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

in Nature by Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira Dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M Lorenz, Viktoria Kunz, Helene Nehring, Thamara N Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G Doll, Emily L Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M Wehman, Thiago C Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B Sathian, David B Konrad, Douglas F Covey, Bernhard Michalke, Kurt Bommert, Ralf C Bargou, Ana Garcia-Saez, Derek A Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad, José Pedro Friedmann Angeli

TLDR

  • The study reveals that 7-dehydrocholesterol (7-DHC) has an anti-ferroptotic effect in cancer cells, which may allow them to escape ferroptosis and grow more aggressively.
  • This raises potential therapeutic implications for targeting 7-DHC levels or activity to enhance ferroptosis and improve cancer treatment outcomes.

Abstract

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

Overview

  • The study identifies the proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and the unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC) in cancer cells.
  • The study investigates the role of 7-DHC accumulation in inducing a shift towards a ferroptosis-resistant state in tumours, leading to a more aggressive phenotype.
  • The findings provide evidence of a previously unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that allows cancer cells to escape ferroptosis.

Comparative Analysis & Findings

  • The study reveals that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation, but have a prosurvival function in cancer cells.
  • 7-DHC was found to effectively shield (phospho)lipids from autoxidation and subsequent fragmentation due to its far superior reactivity towards peroxyl radicals.
  • Validation of the findings was demonstrated in neuroblastoma and Burkitt's lymphoma xenografts, where 7-DHC accumulation led to a shift towards a ferroptosis-resistant state and a more aggressive tumour phenotype.

Implications and Future Directions

  • The study suggests that cancer cells may exploit the antiferroptotic activity of 7-DHC to escape ferroptosis, leading to more aggressive tumour growth and therapy resistance.
  • Future research could focus on the potential therapeutic implications of targeting 7-DHC levels or its activity to enhance ferroptosis and improve cancer treatment outcomes.
  • The study highlights the need for further research into the metabolic adaptation of tumours and the role of lipid metabolism in cancer cell survival and resistance to therapy.
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