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The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis

Author

Listed:
  • Kirill Bersuker

    (University of California, Berkeley)

  • Joseph M. Hendricks

    (University of California, Berkeley)

  • Zhipeng Li

    (University of California, Berkeley)

  • Leslie Magtanong

    (Stanford University)

  • Breanna Ford

    (University of California, Berkeley
    University of California, Berkeley
    University of California, Berkeley)

  • Peter H. Tang

    (Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine)

  • Melissa A. Roberts

    (University of California, Berkeley)

  • Bingqi Tong

    (University of California, Berkeley)

  • Thomas J. Maimone

    (University of California, Berkeley)

  • Roberto Zoncu

    (University of California, Berkeley)

  • Michael C. Bassik

    (Stanford University School of Medicine)

  • Daniel K. Nomura

    (University of California, Berkeley
    University of California, Berkeley
    University of California, Berkeley)

  • Scott J. Dixon

    (Stanford University)

  • James A. Olzmann

    (University of California, Berkeley
    Chan Zuckerberg Biohub)

Abstract

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR–Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.

Suggested Citation

  • Kirill Bersuker & Joseph M. Hendricks & Zhipeng Li & Leslie Magtanong & Breanna Ford & Peter H. Tang & Melissa A. Roberts & Bingqi Tong & Thomas J. Maimone & Roberto Zoncu & Michael C. Bassik & Daniel, 2019. "The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis," Nature, Nature, vol. 575(7784), pages 688-692, November.
  • Handle: RePEc:nat:nature:v:575:y:2019:i:7784:d:10.1038_s41586-019-1705-2
    DOI: 10.1038/s41586-019-1705-2
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    Cited by:

    1. Yun Lv & Chunhui Liang & Qichao Sun & Jing Zhu & Haiyan Xu & Xiaoqing Li & Yao-yao Li & Qihai Wang & Huiqing Yuan & Bo Chu & Deyu Zhu, 2023. "Structural insights into FSP1 catalysis and ferroptosis inhibition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Samya Van Coillie & Emily Van San & Ines Goetschalckx & Bartosz Wiernicki & Banibrata Mukhopadhyay & Wulf Tonnus & Sze Men Choi & Ria Roelandt & Catalina Dumitrascu & Ludwig Lamberts & Geert Dams & Wa, 2022. "Targeting ferroptosis protects against experimental (multi)organ dysfunction and death," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Juliane Tschuck & Vidya Padmanabhan Nair & Ana Galhoz & Carole Zaratiegui & Hin-Man Tai & Gabriele Ciceri & Ina Rothenaigner & Jason Tchieu & Brent R. Stockwell & Lorenz Studer & Daphne S. Cabianca & , 2024. "Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Juliane Tschuck & Lea Theilacker & Ina Rothenaigner & Stefanie A. I. Weiß & Banu Akdogan & Van Thanh Lam & Constanze Müller & Roman Graf & Stefanie Brandner & Christian Pütz & Tamara Rieder & Philippe, 2023. "Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Nathan P. Ward & Sang Jun Yoon & Tyce Flynn & Amanda M. Sherwood & Maddison A. Olley & Juliana Madej & Gina M. DeNicola, 2024. "Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Mihee Oh & Seo Young Jang & Ji-Yoon Lee & Jong Woo Kim & Youngae Jung & Jiwoo Kim & Jinho Seo & Tae-Su Han & Eunji Jang & Hye Young Son & Dain Kim & Min Wook Kim & Jin-Sung Park & Kwon-Ho Song & Kyoun, 2023. "The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Da-Yun Jin & Xuejie Chen & Yizhou Liu & Craig M. Williams & Lars C. Pedersen & Darrel W. Stafford & Jian-Ke Tie, 2023. "A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Pranavi Koppula & Guang Lei & Yilei Zhang & Yuelong Yan & Chao Mao & Lavanya Kondiparthi & Jiejun Shi & Xiaoguang Liu & Amber Horbath & Molina Das & Wei Li & Masha V. Poyurovsky & Kellen Olszewski & B, 2022. "A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Xinyi Shan & Jiahuan Li & Jiahao Liu & Baoli Feng & Ting Zhang & Qian Liu & Huixin Ma & Honghong Wu & Hao Wu, 2023. "Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Wei Yang & Bo Mu & Jing You & Chenyu Tian & Huachao Bin & Zhiqiang Xu & Liting Zhang & Ronggang Ma & Ming Wu & Guo Zhang & Chong Huang & Linli Li & Zhenhua Shao & Lunzhi Dai & Laurent Désaubry & Sheng, 2022. "Non-classical ferroptosis inhibition by a small molecule targeting PHB2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    12. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    13. Xin Chen & Jun Huang & Chunhua Yu & Jiao Liu & Wanli Gao & Jingbo Li & Xinxin Song & Zhuan Zhou & Changfeng Li & Yangchun Xie & Guido Kroemer & Jinbao Liu & Daolin Tang & Rui Kang, 2022. "A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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