IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-35294-2.html
   My bibliography  Save this article

Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Author

Listed:
  • Wei Yang

    (Sichuan University)

  • Bo Mu

    (Sichuan University
    North Sichuan Medical College)

  • Jing You

    (Sichuan University)

  • Chenyu Tian

    (Sichuan University)

  • Huachao Bin

    (Sichuan University)

  • Zhiqiang Xu

    (Sichuan University)

  • Liting Zhang

    (Sichuan University)

  • Ronggang Ma

    (Sichuan University)

  • Ming Wu

    (Sichuan University)

  • Guo Zhang

    (Sichuan University)

  • Chong Huang

    (Sichuan University)

  • Linli Li

    (Sichuan University)

  • Zhenhua Shao

    (Sichuan University)

  • Lunzhi Dai

    (Sichuan University)

  • Laurent Désaubry

    (INSERM-University of Strasbourg, Center of Research in Biomedicine of Strasbourg (CRBS))

  • Shengyong Yang

    (Sichuan University)

Abstract

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35294-2
    DOI: 10.1038/s41467-022-35294-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-35294-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-35294-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Joseph D. Mancias & Xiaoxu Wang & Steven P. Gygi & J. Wade Harper & Alec C. Kimmelman, 2014. "Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy," Nature, Nature, vol. 509(7498), pages 105-109, May.
    2. 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.
    3. Sebastian Doll & Florencio Porto Freitas & Ron Shah & Maceler Aldrovandi & Milene Costa Silva & Irina Ingold & Andrea Goya Grocin & Thamara Nishida Xavier da Silva & Elena Panzilius & Christina H. Sch, 2019. "FSP1 is a glutathione-independent ferroptosis suppressor," Nature, Nature, vol. 575(7784), pages 693-698, November.
    4. Chao Mao & Xiaoguang Liu & Yilei Zhang & Guang Lei & Yuelong Yan & Hyemin Lee & Pranavi Koppula & Shiqi Wu & Li Zhuang & Bingliang Fang & Masha V. Poyurovsky & Kellen Olszewski & Boyi Gan, 2021. "DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer," Nature, Nature, vol. 593(7860), pages 586-590, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    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. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. Yandi Wu & Tongsheng Huang & Xinghui Li & Conghui Shen & Honglin Ren & Haiping Wang & Teng Wu & Xinlu Fu & Shijie Deng & Ziqi Feng & Shijie Xiong & Hui Li & Saifei Gao & Zhenyu Yang & Fei Gao & Lele D, 2023. "Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. 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.
    9. 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.
    10. Giovanni Tosi & Alessandro Paoli & Gaia Zuccolotto & Emilia Turco & Manuela Simonato & Daniela Tosoni & Francesco Tucci & Pietro Lugato & Monica Giomo & Nicola Elvassore & Antonio Rosato & Paola Cogo , 2024. "Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    11. 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.
    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. 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.
    14. 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.
    15. Dan Fu & Wenming Wang & Yan Zhang & Fan Zhang & Pinyi Yang & Chun Yang & Yufei Tian & Renqi Yao & Jingwu Jian & Zixian Sun & Nan Zhang & Zhiyu Ni & Zihe Rao & Lei Zhao & Yu Guo, 2024. "Self-assembling nanoparticle engineered from the ferritinophagy complex as a rabies virus vaccine candidate," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    16. Di-Yang Sun & Wen-Bin Wu & Jian-Jin Wu & Yu Shi & Jia-Jun Xu & Shen-Xi Ouyang & Chen Chi & Yi Shi & Qing-Xin Ji & Jin-Hao Miao & Jiang-Tao Fu & Jie Tong & Ping-Ping Zhang & Jia-Bao Zhang & Zhi-Yong Li, 2024. "Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    17. Yuelong Yan & Hongqi Teng & Qinglei Hang & Lavanya Kondiparthi & Guang Lei & Amber Horbath & Xiaoguang Liu & Chao Mao & Shiqi Wu & Li Zhuang & M. James You & Masha V. Poyurovsky & Li Ma & Kellen Olsze, 2023. "SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Xiaoting Zhou & You-Kyung Lee & Xianting Li & Henry Kim & Carlos Sanchez-Priego & Xian Han & Haiyan Tan & Suiping Zhou & Yingxue Fu & Kerry Purtell & Qian Wang & Gay R. Holstein & Beisha Tang & Junmin, 2024. "Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    19. Jun Jiang & Lili Yang & Qianqian Xie & Xi Liu & Jie Jiang & Jie Zhang & Shuping Zhang & Huizhen Zheng & Wenjie Li & Xiaoming Cai & Sijin Liu & Ruibin Li, 2024. "Synthetic vectors for activating the driving axis of ferroptosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    20. Zifan Ye & Lei Fu & Shuangyu Li & Ziying Chen & Jianhong Ouyang & Xinci Shang & Yanli Liu & Lianghui Gao & Yipeng Wang, 2024. "Synergistic collaboration between AMPs and non-direct antimicrobial cationic peptides," Nature Communications, Nature, vol. 15(1), pages 1-26, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35294-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.