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Integrative multi-omic analysis of radiation-induced skin injury reveals the alteration of fatty acid metabolism in early response of ionizing radiation

  • Author Footnotes
    1 These authors contributed equally to this work.
    Wenling Tu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China

    School of Bioscience and Technology, Chengdu Medical College, Chengdu, China

    NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Shaokai Tang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Tao Yan
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
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  • Yahui Feng
    Affiliations
    The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
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  • Wei Mo
    Affiliations
    School of Radiation Medicine and Protection, State Key Laboratory of Radiation Medicine, Soochow University, Suzhou, China
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  • Bin Song
    Affiliations
    Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
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  • Jinlong Wang
    Affiliations
    School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
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  • Shuanghua Cheng
    Affiliations
    The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
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  • Fenghao Geng
    Affiliations
    Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
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  • Yuhong Shi
    Affiliations
    The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
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  • Daojiang Yu
    Affiliations
    The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
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  • Shuyu Zhang
    Correspondence
    Correspondence to: Department of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
    Affiliations
    Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu, China

    The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China

    Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China

    NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Cutaneous fatty acid metabolism was altered in the early response of ionizing radiation.
      • Fatty acid metabolism-associated ACADVL is involved in radiation-induced cell death.

      Abstract

      Background

      Radiation-induced skin injury is a serious concern during radiotherapy and accidental exposure to radiation.

      Objective

      This study aims to investigate the molecular events in early response to ionizing radiation of skin tissues and underlying mechanism.

      Methods

      Mice and rats were irradiated with an electron beam. Skin tissues were used for liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, mRNA-Seq and single-cell RNA sequencing (scRNA-Seq). Human keratinocytes (HaCaT) and skin fibroblasts (WS1) were used for functional studies.

      Results

      The integrated analysis of metabolomics and transcriptomics showed that 6 key fatty acid-associated metabolites, 9 key fatty acid-associated genes and multiple fatty acid-associated pathways were most obviously enriched and increased in the irradiated skins. Among them, acyl-CoA dehydrogenase very long chain (ACADVL) was investigated in greater detail due to its most obvious expression difference and significance in fatty acid metabolism. ScRNA-Seq of rat skin from irradiated individuals revealed that ACADVL was expressed in all subpopulations of skin tissues, with variations at different timepoints after radiation. Immunohistochemistry confirmed an increased ACADVL expression in the epidermis from human sample and various animal models, including monkeys, rats and mice. The knockdown of ACADVL increased the radiosensitivity of human keratinocytes and human skin fibroblasts. Silencing of ACADVL facilitated the expression of apoptosis and pyroptosis-related proteins following ionizing radiation.

      Conclusion

      This study illustrated that cutaneous fatty acid metabolism was altered in the early response of ionizing radiation, and fatty acid metabolism-associated ACADVL is involved in radiation-induced cell death.

      Keywords

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