逆转座元件异常活化在放疗晚反应中的研究进展与展望

温雅雯; 孙利 综述; 郑向鹏 审校

doi:10.19401/j.cnki.1007-3639.2025.08.010

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逆转座元件异常活化在放疗晚反应中的研究进展与展望

综述 | 更新时间：2025-12-31

- 逆转座元件异常活化在放疗晚反应中的研究进展与展望
- Derepression of retrotransposable elements in the development of radiation-induced late effects: advancements and perspective
- 中国癌症杂志 2025年35卷第8期页码：808-814
- 作者机构：
  
  复旦大学附属华东医院肿瘤放疗科，上海 200040
- 作者简介：
  
  [ "温雅雯（ORCID: 0009-0009-3532-6098），硕士研究生在读。" ]
  郑向鹏（ORCID: 0000-0001-9953-2143），博士，主任医师，复旦大学附属华东医院肿瘤放疗科主任。
- 基金信息：
  
  上海市抗癌协会“雏鹰”计划(SACA-CY24A03)
- DOI：10.19401/j.cnki.1007-3639.2025.08.010
  中图分类号： R730.55
- 收稿：2025-03-13，
  
  修回：2025-06-11，
  
  纸质出版：2025-08-30
- 稿件说明：
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温雅雯, 孙利综述, 郑向鹏审校. 逆转座元件异常活化在放疗晚反应中的研究进展与展望[J]. 中国癌症杂志, 2025,35(8):808-814.

Yawen WEN, Li SUN, Xiangpeng ZHENG. Derepression of retrotransposable elements in the development of radiation-induced late effects: advancements and perspective[J]. China Oncology, 2025, 35(8): 808-814.
温雅雯, 孙利综述, 郑向鹏审校. 逆转座元件异常活化在放疗晚反应中的研究进展与展望[J]. 中国癌症杂志, 2025,35(8):808-814. DOI： 10.19401/j.cnki.1007-3639.2025.08.010.

Yawen WEN, Li SUN, Xiangpeng ZHENG. Derepression of retrotransposable elements in the development of radiation-induced late effects: advancements and perspective[J]. China Oncology, 2025, 35(8): 808-814. DOI： 10.19401/j.cnki.1007-3639.2025.08.010.

摘要

放疗导致晚反应或延迟反应对患者的长期生活质量影响甚大，然而目前对其发生和发展机制的认识非常有限，缺乏有效的风险预测方法和预防干预措施。基于放射生物学和放疗诱导衰老模型的研究提示，放疗能够改变晚反应组织细胞内的表观遗传学特征，诱发逆转座元件序列（特别是内源性逆转录病毒元件）的表达活化，进而触发细胞质内的异常核酸感受器系统（cGAS-STING和MDA5/RIG-I-MAVS）和Ⅰ型干扰素介导的免疫炎症反应。本文对相关研究结果进行综述，认为“放疗-表观遗传学改变-逆转座元件活化”诱导的自身免疫样炎症反应是放疗晚反应发生的不可忽视的机制基础，通过构建基于表观遗传学特征和细胞类型与放疗剂量的晚反应风险模型和发展靶向表观遗传学抑制逆转座元件表达有助于预防或减轻放疗晚反应。

Abstract

Radiotherapy-induced late effects (RILE) or delayed reactions have significant impacts on patients' long-term quality of life. However

current understanding of their developmental mechanisms remains limited

with a lack of effective risk prediction models and preventive interventions. Radiobiological studies and radiation-induced senescence models have revealed that radiotherapy can alter the epigenetic characteristics in late-responding tissue cells

leading to derepression of retrotransposable elements (particularly endogenous retroviral elements)

subsequent activation of cytoplasmic nucleic acid sensor systems (cGAS-STING

MDA5/RIG-I-MAVS) and type Ⅰ interferon-mediated immune-inflammatory responses. This review summarized relevant research findings

proposing that the autoimmune-like inflammatory response induced by the 'radiotherapy-epigenetic alteration-retrotransposable element activation’ cascade is an underinvestigated mechanistic basis in the development of RILE. Constructing risk prediction models for late effects based on epigenetic signatures

cell type

and radiation dose

along with developing strategies to epigenetically suppress retrotransposable element expression

holds promise for preventing or mitigating RILE.

关键词

Keywords

references

ICRP A O B O , STEWART F A , AKLEYEV A V , et al . ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs: threshold doses for tissue reactions in a radiation protection context [J ] . Ann ICRP , 2012 , 41 ( 1/2 ): 1 - 322 .

BENTZEN S M . Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology [J ] . Nat Rev Cancer , 2006 , 6 ( 9 ): 702 - 713 . DOI: 10.1038/nrc1950 http://doi.org/10.1038/nrc1950

CARDELLI M . The epigenetic alterations of endogenous retroelements in aging [J ] . Mech Ageing Dev , 2018 , 174 : 30 - 46 . DOI: S0047-6374(17)30291-9 http://doi.org/S0047-6374(17)30291-9

JOHNSON W E . Endogenous retroviruses in the genomics era [J ] . Annu Rev Virol , 2015 , 2 ( 1 ): 135 - 159 . DOI: 10.1146/annurev-virology-100114-054945 http://doi.org/10.1146/annurev-virology-100114-054945

DOPKINS N , NIXON D F . Activation of human endogenous retroviruses and its physiological consequences [J ] . Nat Rev Mol Cell Biol , 2024 , 25 ( 3 ): 212 - 222 .

DOPKINS N , O’MARA M M , LAWRENCE E , et al . A field guide to endogenous retrovirus regulatory networks [J ] . Mol Cell , 2022 , 82 ( 20 ): 3763 - 3768 . DOI: 10.1016/j.molcel.2022.09.011 http://doi.org/10.1016/j.molcel.2022.09.011

MERENCIANO M , LARUE A , GARAMBOIS C , et al . Exploring the relationship of transposable elements and ageing: causes and consequences [J ] . Genome Biol Evol , 2025 , 17 ( 6 ): evaf088.

ZHAO X R , ZONG J B , LIU Y X , et al . Endogenous retroviruses unveiled: a comprehensive review of inflammatory signaling/senescence-related pathways and therapeutic strategies [J ] . Aging Dis , 2024 , 16 ( 2 ): 738 - 756 .

WANG F , LI K Y , WANG W S , et al . Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy [J ] . Cell Death Dis , 2024 , 15 ( 10 ): 779 . DOI: 10.1038/s41419-024-07175-7 http://doi.org/10.1038/s41419-024-07175-7

SCHMIDLEITHNER L , STÜVE P , FEUERER M . Transposable elements as instructors of the immune system [J ] . Nat Rev Immunol , 2025 .

KASSIOTIS G . The immunological conundrum of endogenous retroelements [J ] . Annu Rev Immunol , 2023 , 41 : 99 - 125 .

LIU X Q , LIU Z P , WU Z M , et al . Resurrection of endogenous retroviruses during aging reinforces senescence [J ] . Cell , 2023 , 186 ( 2 ): 287 - 304 .e26. DOI: 10.1016/j.cell.2022.12.017 http://doi.org/10.1016/j.cell.2022.12.017

MIN X L , ZHENG M L , YU Y Q , et al . Ultraviolet light induces HERV expression to activate RIG-I signalling pathway in keratinocytes [J ] . Exp Dermatol , 2022 , 31 ( 8 ): 1165 - 1176 . DOI: 10.1111/exd.14568 http://doi.org/10.1111/exd.14568

WANG R C , LI H D , WU J F , et al . Gut stem cell necroptosis by genome instability triggers bowel inflammation [J ] . Nature , 2020 , 580 ( 7803 ): 386 - 390 .

MISHRA S , DEY A A , KESAVARDHANA S . Z-nucleic acid sensing and activation of ZBP1 in cellular physiology and disease pathogenesis [J ] . Immunol Rev , 2025 , 329 ( 1 ): e13437 .

LIU Y , MOLCHANOV V , ZHAO Y G , et al . H3K9me3 loss and ERVs activation as hallmarks for osteoarthritis progression and knee joint aging [J ] . Osteoarthritis Cartilage , 2025 , 33 ( 1 ): 128 - 133 .

CABRÉ N , FONDEVILA M F , WEI W C , et al . Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease [J ] . J Clin Invest , 2025 , 135 ( 13 ): e188541 .

MEEVASSANA J , SERIRODOM S , PRABSATTRU P , et al . Alu repetitive sequence CpG methylation changes in burn scars [J ] . Burns , 2022 , 48 ( 6 ): 1417 - 1424 .

SHANKARAPPA B , MAHADEVAN J , MURTHY P , et al . Hypomethylation of long interspersed nucleotide elements and aldehyde dehydrogenase in patients of alcohol use disorder with cirrhosis [J ] . DNA Cell Biol , 2023 , 42 ( 7 ): 364 - 371 .

DHILLON P , MULHOLLAND K A , HU H L , et al . Increased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development [J ] . Nat Commun , 2023 , 14 ( 1 ): 559 . DOI: 10.1038/s41467-023-36212-w http://doi.org/10.1038/s41467-023-36212-w

RODRIGUEZ-SANABRIA J S , ROSAS-CAMPOS R , VÁZQUEZ-ESQUEDA Á , et al . H3K9me3 demethylation by JMJD2B is regulated by pirfenidone resulting in improved NASH [J ] . Sci Rep , 2024 , 14 ( 1 ): 24714 .

SCHMIDT J , ERFLE V , MÜLLER W A . Activation of endogenous C-type retroviral genomes by internal alpha-irradiation of mice with 224Radium [J ] . Radiat Environ Biophys , 1985 , 24 ( 1 ): 17 - 25 .

The 2007 recommendations of the international commission on radiological protection . ICRP publication 103 [J ] . Ann ICRP , 2007, 37 ( 2/3/4 ): 1 - 332 .

LEE H G , RONE J M , LI Z R , et al . Disease-associated astrocyte epigenetic memory promotes CNS pathology [J ] . bioRxiv , 2024 : 2024 .01.04.574196.

BARNES B M , SHYNE A , GUNN D A , et al . Epigenetics and ultraviolet radiation: implications for skin ageing and carcinogenesis [J ] . Skin Health Dis , 2024 , 4 ( 6 ): e410 .

BIAN X W , PIIPPONEN M , LIU Z , et al . Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors [J ] . Nat Commun , 2024 , 15 ( 1 ): 9286 . DOI: 10.1038/s41467-024-53295-1 http://doi.org/10.1038/s41467-024-53295-1

PARK J , LEE H J , HAN Y K , et al . Identification of DNA methylation biomarkers for evaluating cardiovascular disease risk from epigenome profiles altered by low-dose ionizing radiation [J ] . Clin Epigenetics , 2024 , 16 ( 1 ): 19 . DOI: 10.1186/s13148-024-01630-0 http://doi.org/10.1186/s13148-024-01630-0

AHMAD CHAUDHRY M , OMARUDDIN R A . Differential DNA methylation alterations in radiation-sensitive and-resistant cells [J ] . DNA Cell Biol , 2012 , 31 ( 6 ): 908 - 916 .

VARSHNEY D , VAVROVA-ANDERSON J , OLER A J , et al . SINE transcription by RNA polymerase Ⅲ is suppressed by histone methylation but not by DNA methylation [J ] . Nat Commun , 2015 , 6 : 6569 .

BROCKS D , SCHMIDT C R , DASKALAKIS M , et al . DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats [J ] . Nat Genet , 2017 , 49 ( 7 ): 1052 - 1060 . DOI: 10.1038/ng.3889 http://doi.org/10.1038/ng.3889

MAGER D L , LORINCZ M C . Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses [J ] . Nat Genet , 2017 , 49 ( 7 ): 974 - 975 . DOI: 10.1038/ng.3902 http://doi.org/10.1038/ng.3902

YAO Y , CHEN L F , LI J , et al . Altered DNA methylation and gene expression profiles in radiation-induced heart fibrosis of sprague-dawley rats [J ] . Radiat Res , 2022 , 198 ( 2 ): 154 - 161 .

QIU Y Y , GAO Y Y , YU D J , et al . Genome-wide analysis reveals zinc transporter ZIP9 regulated by DNA methylation promotes radiation-induced skin fibrosis via the TGF-β signaling pathway [J ] . J Invest Dermatol , 2020 , 140 ( 1 ): 94 - 102 .e7. DOI: S0022-202X(19)31795-6 http://doi.org/S0022-202X(19)31795-6

BECKER B V , KAATSCH L , OBERMAIR R , et al . X-ray irradiation induces subtle changes in the genome-wide distribution of DNA hydroxymethylation with opposing trends in genic and intergenic regions [J ] . Epigenetics , 2019 , 14 ( 1 ): 81 - 93 . DOI: 10.1080/15592294.2019.1568807 http://doi.org/10.1080/15592294.2019.1568807

TERRAZZINO S , DEANTONIO L , CARGNIN S , et al . DNA methyltransferase gene polymorphisms for prediction of radiation-induced skin fibrosis after treatment of breast cancer: a multifactorial genetic approach [J ] . Cancer Res Treat , 2017 , 49 ( 2 ): 464 - 472 . DOI: 10.4143/crt.2016.256 http://doi.org/10.4143/crt.2016.256

ISHAK C A , MARSHALL A E , PASSOS D T , et al . An RB-EZH2 complex mediates silencing of repetitive DNA sequences [J ] . Mol Cell , 2016 , 64 ( 6 ): 1074 - 1087 . DOI: S1097-2765(16)30666-9 http://doi.org/S1097-2765(16)30666-9

ZHANG Y Y , YU C , AGBORBESONG E , et al . Downregulation of EZH2 promotes renal epithelial cellular senescence and kidney aging [J ] . FASEB J , 2025 , 39 ( 9 ): e70605 .

SHAO Z Y , LU J W , KHUDAVERDYAN N , et al . Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation [J ] . Nat Commun , 2024 , 15 ( 1 ): 6815 . DOI: 10.1038/s41467-024-51246-4 http://doi.org/10.1038/s41467-024-51246-4

GEHRS S , GU Z G , HEY J , et al . DNMT3A-dependent DNA methylation shapes the endothelial enhancer landscape [J ] . Nucleic Acids Res , 2025 , 53 ( 10 ): gkaf435.

CAMERON E E , BACHMAN K E , MYÖHÄNEN S , et al . Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer [J ] . Nat Genet , 1999 , 21 ( 1 ): 103 - 107 .

HUANG W J , HICKSON L J , EIRIN A , et al . Cellular senescence: the good, the bad and the unknown [J ] . Nat Rev Nephrol , 2022 , 18 ( 10 ): 611 - 627 . DOI: 10.1038/s41581-022-00601-z http://doi.org/10.1038/s41581-022-00601-z

SURYADEVARA V , HUDGINS A D , RAJESH A , et al . SenNet recommendations for detecting senescent cells in different tissues [J ] . Nat Rev Mol Cell Biol , 2024 , 25 ( 12 ): 1001 - 1023 .

KIM J H , BROWN S L , GORDON M N . Radiation-induced senescence: therapeutic opportunities [J ] . Radiat Oncol , 2023 , 18 ( 1 ): 10 . DOI: 10.1186/s13014-022-02184-2 http://doi.org/10.1186/s13014-022-02184-2

BLOKLAND K E C , WATERS D W , SCHULIGA M , et al . Senescence of IPF lung fibroblasts disrupt alveolar epithelial cell proliferation and promote migration in wound healing [J ] . Pharmaceutics , 2020 , 12 ( 4 ): 389 .

RYAN P , LEE J . In vitro senescence and senolytic functional assays [J ] . Biomater Sci , 2025 , 13 ( 13 ): 3509 - 3531 .

ZHU J J , AO X K , LIU Y H , et al . TNKS1BP1 mediates AEC Ⅱ senescence and radiation induced lung injury through suppressing EEF2 degradation [J ] . Respir Res , 2024 , 25 ( 1 ): 299 .

DE CECCO M , ITO T , PETRASHEN A P , et al . L1 drives IFN in senescent cells and promotes age-associated inflammation [J ] . Nature , 2019 , 566 ( 7742 ): 73 - 78 .

VAN METER M , KASHYAP M , REZAZADEH S , et al . SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age [J ] . Nat Commun , 2014 , 5 : 5011 . DOI: 10.1038/ncomms6011 http://doi.org/10.1038/ncomms6011

MAO J , ZHANG Q , ZHUANG Y , et al . Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging [J ] . Nat Aging , 2024 , 4 ( 12 ): 1794 - 1812 . DOI: 10.1038/s43587-024-00745-6 http://doi.org/10.1038/s43587-024-00745-6

KREILING J A . Dysregulation of endogenous retroviruses triggers aging and senescence [J ] . Nat Aging , 2024 , 4 ( 12 ): 1670 - 1672 . DOI: 10.1038/s43587-024-00759-0 http://doi.org/10.1038/s43587-024-00759-0

YAHYAPOUR R , AMINI P , REZAPOUR S , et al . Radiation-induced inflammation and autoimmune diseases [J ] . Mil Med Res , 2018 , 5 ( 1 ): 9 . DOI: 10.1186/s40779-018-0156-7 http://doi.org/10.1186/s40779-018-0156-7

VIRET C , BYNOE M S . Human endogenous retroviruses expression in autoimmunity [J ] . Yale J Biol Med , 2024 , 97 ( 4 ): 521 - 528 . DOI: 10.59249/OIKF8301 http://doi.org/10.59249/OIKF8301

PEZONE A , OLIVIERI F , NAPOLI M V , et al . Inflammation and DNA damage: cause, effect or both [J ] . Nat Rev Rheumatol , 2023 , 19 ( 4 ): 200 - 211 . DOI: 10.1038/s41584-022-00905-1 http://doi.org/10.1038/s41584-022-00905-1

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