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The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis

Author

Listed:
  • Zhi Lin

    (Central South University)

  • Jiao Liu

    (Third Affiliated Hospital of Guangzhou Medical University
    Guangzhou Medical University)

  • Fei Long

    (Central South University)

  • Rui Kang

    (UT Southwestern Medical Center)

  • Guido Kroemer

    (Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France
    Gustave Roussy Cancer Campus
    Hôpital Européen Georges Pompidou)

  • Daolin Tang

    (UT Southwestern Medical Center)

  • Minghua Yang

    (Central South University)

Abstract

Ferroptosis is a type of regulated necrosis caused by unrestricted lipid peroxidation and subsequent plasma membrane rupture. However, the lipid remodeling mechanism that determines sensitivity to ferroptosis remains poorly understood. Here, we report a previously unrecognized role for the lipid flippase solute carrier family 47 member 1 (SLC47A1) as a regulator of lipid remodeling and survival during ferroptosis. Among 49 phospholipid scramblases, flippases, and floppases we analyzed, only SLC47A1 had mRNA that was selectively upregulated in multiple cancer cells exposed to ferroptotic inducers. Large-scale lipidomics and functional analyses revealed that the silencing of SLC47A1 increased RSL3- or erastin-induced ferroptosis by favoring ACSL4-SOAT1–mediated production of polyunsaturated fatty acid cholesterol esters. We identified peroxisome proliferator activated receptor alpha (PPARA) as a transcription factor that transactivates SLC47A1. The depletion of PPARA and SLC47A1 similarly sensitized cells to ferroptosis induction, whereas transfection-enforced re-expression of SLC47A1 restored resistance to ferroptosis in PPARA-deficient cells. Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway increased the anticancer activity of a ferroptosis inducer in mice. These findings establish a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance.

Suggested Citation

  • Zhi Lin & Jiao Liu & Fei Long & Rui Kang & Guido Kroemer & Daolin Tang & Minghua Yang, 2022. "The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35707-2
    DOI: 10.1038/s41467-022-35707-2
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    References listed on IDEAS

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    1. 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.
    2. Jiao Liu & Xinxin Song & Feimei Kuang & Qiuhong Zhang & Yangchun Xie & Rui Kang & Guido Kroemer & Daolin Tang, 2021. "NUPR1 is a critical repressor of ferroptosis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Enyong Dai & Leng Han & Jiao Liu & Yangchun Xie & Herbert J. Zeh & Rui Kang & Lulu Bai & Daolin Tang, 2020. "Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. Tao Long & Yingyuan Sun & Abdirahman Hassan & Xiaofeng Qi & Xiaochun Li, 2020. "Structure of nevanimibe-bound tetrameric human ACAT1," Nature, Nature, vol. 581(7808), pages 339-343, May.
    5. Yilong Zou & Whitney S. Henry & Emily L. Ricq & Emily T. Graham & Vaishnavi V. Phadnis & Pema Maretich & Sateja Paradkar & Natalie Boehnke & Amy A. Deik & Ferenc Reinhardt & John K. Eaton & Bryan Ferg, 2020. "Plasticity of ether lipids promotes ferroptosis susceptibility and evasion," Nature, Nature, vol. 585(7826), pages 603-608, September.
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    1. Keith Woodley & Laura S. Dillingh & George Giotopoulos & Pedro Madrigal & Kevin M. Rattigan & Céline Philippe & Vilma Dembitz & Aoife M. S. Magee & Ryan Asby & Louie N. van de Lagemaat & Christopher M, 2023. "Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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